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373 Cards in this Set
- Front
- Back
how much of the human genome encodes proteins?
|
less than two percent
25,000 genes that can give rise to more than 100,000 proteins via alternative splicing |
|
define genomics
|
study of all the genes in the genome and their interactions
|
|
how much DNA is shared between any two individuals?
|
more than 99.5%
diversity in humans is encoded in less than 0.5% of DNA |
|
what are the two most common forms of DNA variations in the human genome?
|
single-nucleotide polymorphisms (SNPs)
copy number variations (CNVs) |
|
what are SNPs?
|
single-nucleotide polymorphisms
variation of a single isolated nucleotide position - almost always biallelic |
|
how do SNPs related to disease?
|
could alter the gene product and predispose to the disease
more commonly, SNPs are just a marker that is co-inherited with a disease-associated gene as a result of physical proximity |
|
define linkage disequilibrium
|
the non-random association of alleles at two or more loci
|
|
what are CNVs?
|
copy number variations
form of genetic variation consisting of different numbers of large contiguous stretches of DNA from 1000 base pairs to millions of base pairs |
|
define epigenetics
|
heritable changes in gene expression that are not caused by alterations in DNA sequence
involved in tissue-specific expression of genes and genomic imprinting |
|
define proteomics
|
the study and measurement of all proteins expressed in a cell or tissue
|
|
what are miRNAs?
|
micro RNAs
small RNA molecules that do not encode proteins, but instead inhibit gene expression after transcription |
|
how are mature miRNA molecules produced?
|
transcribed to produce primary miRNA transcripts, which are then processed in the nucleus to form pre-miRNA
pre-miRNA is transported to the cytoplasm via specific transporter proteins, where Dicer generates mature miRNAs |
|
what cytoplasmic enzyme is responsible for cleaving pre-miRNA to form mature miRNA?
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Dicer
|
|
what is the function of Dicer?
|
Dicer is a cytoplasmic enzyme that is responsible for cleaving pre-miRNA to form mature miRNA
|
|
into what multiprotein complex is mature, single-stranded miRNA incorporated? what does this complex do?
|
RNA-induced silencing complex (RISC)
base-pairing between the complexed miRNA and its target mRNA directs the RISC to either cause mRNA cleavage or repress its translation |
|
what is RISC?
|
RNA-induced silencing complex
multiprotein complex that complexes with miRNA and, via base-pairing between the miRNA strand and its target mRNA, either cleaves mRNA or represses its translation |
|
how many genes can be silenced by a single miRNA molecule?
|
a single miRNA molecule can silence many target genes
|
|
what are siRNAs?
|
small interfering RNAs
synthetic miRNAs - behave identically to miRNAs except that by definition they must have been introduced into the cell by researchers/investigators |
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what is the estimated lifetime frequency of genetic diseases?
|
670 per 1000
|
|
what are mendelian disorders?
|
disorders related to mutations in a single gene that has large effects
|
|
from what do chromosomal disorders arise?
|
structural or numerical alteration in the autosomes and sex chromosomes
|
|
from what do complex multigenic disorders arise?
|
interactions between multiple variant forms of genes and environmental factors
only when several polymorphisms are present in an individual does disease occur |
|
what is GWAS?
|
genome wide association studies
systematic method of identifying disease-associated polymorphisms |
|
define mutation
|
a permanent change in the DNA
|
|
what is the difference between mutations in germ cells vs. mutations in somatic cells?
|
in germ cells, mutations are transmitted to progeny and thus lead to inherited disease
in somatic cells, mutations are not transmitted to progeny, but instead cause cancers and congenital malformations |
|
define point mutation
|
a single nucleotide base is substituted by a different base
|
|
define frameshift mutations
|
insertion or deletion of one or two base pairs (importantly not a multiple of 3) from the DNA leading to alterations in the reading frame of the DNA strand
|
|
what is a missense mutation?
|
mutation that leads to the replacement of one amino acid by another
changes the meaning of the sequence of encoded protein |
|
what is a conservative missense mutation?
|
substitution of one amino acid by another, where the substituted amino acid has little effect on the function of the protein
|
|
what is a nonconservative missense mutation?
|
substitution of one amino acid by another, where the substituted amino acid is very different from the original one and therefore has large effects on the function of the protein
|
|
what is a nonsense mutation?
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a point mutation that changes an amino acid codon to a chain terminator (stop) codon
|
|
what are trinucleotide-repeat mutations?
|
amplification of a sequence of three nucleotides
although the specific nucleotide sequence varies between disorders, almost all affected sequences are some combination of guanine (G) and cytosine (C) |
|
aside from the amplification of a specific nucleotide sequence, what is the other distinguishing feature of trinucleotide-repeat mutation?
|
they are dynamic (i.e. the degree of amplification increases during gametogenesis)
|
|
what single-gene disorders have nonclassic patterns of inheritance?
|
disorders resulting from:
- triplet repeat mutations - mutations in mitochondrial DNA - transmission influenced by genomic imprinting or gonadal mosaicism |
|
what is a hereditary disorder?
|
disorder derived from one's parents and transmitted in the germ line through the generations
aka familial disorder |
|
define congenital
|
means born with
|
|
what is sickle cell trait?
|
in an individual with heterozygous for the mutant (HbS) gene, only a proportion of the hemoglobin is HbS (the remainder being the normal HbA)
red cell sickling occurs in this situation only when there is exposure to lowered oxygen tension |
|
what is codominance?
|
condition in which both alleles of a gene pair contribute to the phenotype seen
e.g. histocompatibility and blood group antigens |
|
what is pleiotropism?
|
a single mutant gene leading to many end effects
|
|
what is genetic heterogeneity?
|
mutations at several genetic loci produce the same trait
|
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what are autosomal dominant disorders?
|
disorder is manifested even in persons with the heterozygous genotype
|
|
in the proportion of patients, afflicted with an autosomal dominant disorder, whose parents are not afflicted with the disorder, how did they inherit it?
|
new mutations involving either the egg or sperm from which they were derived
|
|
what is incomplete penetrance?
|
individual inherits an autosomal dominant mutant gene, but they are phenotypically normal
|
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what is variable expressivity?
|
a trait is seen in all individuals carrying the mutant gene but is expressed differently among individuals
|
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what are the two major categories of nonenzyme proteins affected in autosomal dominant disorders?
|
those involved in regulation of complex metabolic pathways that are subject to feedback inhibition
key structural proteins |
|
what is dominant negative?
|
mutant allele that impairs the function of a normal allele
|
|
what are gain-of-function mutations?
|
gene mutation in which the protein product of the mutant allele acquires new properties not normally associated with the wild-type protein
transmission of disorders produced by gain-of-function mutations is almost always autosomal dominant |
|
what nervous system disorders are autosomal dominant?
|
huntington disease
neurofibromatosis myotonic dystrophy tuberous sclerosis |
|
what urinary disorders follow autosomal dominant inheritance?
|
polycystic kidney disease
|
|
what gastrointestinal disorders follow autosomal dominant inheritance?
|
familial polyposis coli
|
|
what hematopoietic disorders follow autosomal dominant inheritance?
|
hereditary spherocytosis
von Willebrand disease |
|
what skeletal disorders follow autosomal dominant inheritance?
|
marfan syndrome
ehlers-danlos syndrome (some variants) osteogenesis imperfecta achondroplasia |
|
what metabolic disorders follow autosomal dominant inheritance?
|
familial hypercholesterolemia
acute intermittent porphyria |
|
what are autosomal recessive disorders?
|
disorders which result only when both alleles at a given gene locus are mutated
|
|
what are the features that characterize autosomal recessive disorders?
|
trait does not usually affect the parents of the affected individual, but siblings may show the disease
siblings have one chance in four of having the trait if the mutant gene occurs with a low frequency in the population, there is a strong likelihood that the affected individual is the product of a consanguineous marriage |
|
what type of inheritance pattern is followed by disorders resulting in mutated enzymes?
|
autosomal recessive
|
|
what metabolic diseases follow an autosomal recessive inheritance pattern?
|
cystic fibrosis
phenylketonuria galactosemia homocystinuria lysosomal storage diseases alpha1-antitrypsin deficiency wilson disease hemochromatosis glycogen storage diseases |
|
what hematopoietic diseases follow an autosomal recessive inheritance pattern?
|
sickle cell anemia
thalassemias |
|
what endocrine diseases follow an autosomal recessive inheritance pattern?
|
congenital adrenal hyperplasia
|
|
what skeletal diseases follow an autosomal recessive inheritance pattern?
|
ehlers-danlos syndrome (some variants)
alkaptonuria |
|
what nervous system diseases follow an autosomal recessive inheritance pattern?
|
neurogenic muscular atrophies
friedreich ataxia spinal muscular atrophy |
|
what inheritance pattern is followed by all sex-linked disorders?
|
all sex-linked disorders are X-linked and almost all are recessive
|
|
what is meant by the term hemizygous? where does it apply?
|
an individual who has only one member of a chromosome pair or chromosome segment rather than the usual two; refers in particular to X-linked genes in males who under usual circumstances have only one X chromosome
males are said to be hemizygous for X-linked mutant genes because mutant genes on the X do not have corresponding alleles on the Y |
|
how are X-linked disorders carried to the children of an affected man?
|
the affected male cannot transmit the disorder to his sons, but all of his daughters will be carriers
|
|
what musculoskeletal disorders are transferred by an autosomal dominant inheritance pattern?
|
duchenne muscular dystrophy
|
|
what blood disorders are transferred by an autosomal dominant inheritance pattern?
|
hemophilia A and B
chronic granulomatous disease G6P dehydrogenase deficiency |
|
what immune disorders are transferred by an autosomal dominant inheritance pattern?
|
agammaglobulinemia
wiskott-aldrich syndrome |
|
what metabolic disorders are transferred by an autosomal dominant inheritance pattern?
|
diabetes insipidus
lesch-nyhan syndrome |
|
what nervous system disorders are transferred by an autosomal dominant inheritance pattern?
|
fragile-X syndrome
|
|
what enzyme is deficient in phenylketonuria?
|
phenylalanine hydroxylase
|
|
what enzyme is deficient in tay-sachs disease?
|
hexosaminidase A (alpha subunit)
|
|
what enzyme is deficient in severe combined immunodeficiency?
|
adenosine deaminase
|
|
what is caused by alpha1-antitrypsin deficiency?
|
emphysema
liver disease |
|
what protein is deficient in familial hypercholesterolemia?
|
low-density lipoprotein receptor
|
|
what protein is deficient in vitamin D-resistant rickets?
|
vitamin D receptor
|
|
what protein is deficient in alpha-thalassemia?
|
hemoglobin
|
|
what protein is deficient in beta-thalassemia?
|
hemoglobin
|
|
what protein is deficient in sickle cell anemia?
|
hemoglobin
|
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what protein is deficient in osteogenesis imperfecta?
|
collagen
|
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what protein is deficient in ehlers-danlos syndromes?
|
collagen
|
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what protein is deficient in marfan syndrome?
|
fibrillin-1
|
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what protein is deficient in duchenne/becker muscular dystrophy?
|
dystrophin
|
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what protein is deficient in hereditary spherocytosis?
|
spectrin
|
|
what protein is deficient in hemophilia A?
|
factor VIII
|
|
what protein is deficient in hereditary retinoblastoma?
|
Rb protein
|
|
what protein is deficient in neurofibromatosis type I?
|
neurofibromin
|
|
what is the estimated prevalence of Marfan syndrome?
|
1 in 5000
|
|
what type of inheritance pattern is displayed by Marfan syndrome?
|
autosomal dominant inheritance
|
|
what is the major component of microfibrils found in the extracellular matrix?
|
fibrillin
|
|
what is the purpose of fibrillin?
|
it is the major component of microfibrils found in the extracellular matrix, which provide a scaffolding on which tropoelastin is deposited to form elastic fibers
|
|
where are microfibrils particularly abundant?
|
widely distributed in the body, but particularly abundant in the aorta, ligaments, and the ciliary zonules that support the lens
|
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what disorder is caused by a mutation in the FBN1 gene?
|
inherited defect in the extracellular glycoprotein called fibrillin-1
marfan syndrome |
|
what disorder is caused by a mutation in the FBN2 gene?
|
congenital contractural arachnodactyly
|
|
what is the effect of a loss of microfibrils on TGF-beta?
|
leads to abnormal and excessive activation of TGF-beta, since normal microfibrils sequester TGF-beta and thus control the bioavailability of this cytokine
|
|
what is the effect of excessive TGF-beta signalling in Marfan syndrome?
|
has delerious effects on vascular smooth muscle development and the integrity of extracellular matrix
|
|
what are the skeletal abnormalities associated with Marfan syndrome?
|
unusually tall with exceptionally long extremities and long, tapering fingers and toes
joint ligaments in the hands and feet are lax (double jointed) the head is typically dolichocephalic (long-headed) with bossing of the frontal eminences and prominent supraorbital ridges spinal deformities (kyphosis, scoliosis, or rotation/slipping of dorsal/lumbar vertebrae) pectus excavatum (deeply depressed sternum) pigeon-breast deformity |
|
what are the ocular changes associated with Marfan syndrome?
|
ectopia lentis - bilateral subluxation or dislocation (usually outward and upward) of the lens
|
|
what is ectopia lentis?
|
displacement or malposition of the eye's crystalline lens from its normal location
|
|
on finding bilateral ectopia lentis, what disorder should be suspected?
|
Marfan syndrome
|
|
what are the two most common cardiovascular lesions in Marfan syndrome?
|
mitral valve prolapse
dilation of the ascending aorta due to cystic medionecrosis aortic incompetence |
|
what is the effect of weakening the aortic media in Marfans syndrome?
|
predisposes to an intimal tear, which may initiate an intramural hematoma that cleaves the layers of the media to produce aortic dissection
|
|
what are the requirements for clinical diagnosis of Marfans syndrome?
|
must be based on major involvement of two out of four organ systems (skeletal, cardiovascular, ocular, and skin) as well as minor involvement of another organ
|
|
what are Ehlers-Danlos syndromes?
|
clinically and genetically heterogeneous group of disorders that result from some defect in the synthesis or structure of fibrillar collagen
|
|
what happens to skin in Ehlers-Danlos syndrome?
|
becomes hyperextensible
extraordinarily stretchable, extremely fragile, and vulnerable to trauma |
|
what happens to joints in Ehlers-Danlos syndrome?
|
become hypermobile
predisposition to joint dislocation |
|
what are the serious internal complications of Ehlers-Danlos syndrome?
|
rupture of the colon and large arteries (vascular type)
ocular fragility with rupture of cornea and retinal detachment (kyphoscoliosis type) diaphragmatic hernia (classical type) |
|
what are the three important types of Ehlers-Danlos syndrome? what are their causes?
|
classical (I/II) - mutations in genes of type V collagen
vascular (IV) - abnormalities of type 3 collagen kyphoscoliosis (VI) - deficiency of lysyl hydroxylase |
|
what is the defect in kyphoscoliosis type (type VI) Ehlers-Danlos syndrome?
|
deficiency of lysyl hydroxylase
|
|
what is the defect in vascular type (type IV) Ehlers-Danlos syndrome?
|
abnormalities in type III collagen
|
|
what is the defect in classical type (type I/II) Ehlers-Danlos syndrome?
|
abnormalities in type V collagen
|
|
what is the most common autosomal recessive form of Ehlers-Danlos syndrome?
|
kyphoscoliosis type (type VI)
|
|
what type of collagen is rich in blood vessels and intestines?
|
type III collagen
|
|
what is the fundamental defect in the arthrochalasia type of Ehlers-Danlos syndrome?
|
conversion of type I procollagen to collagen
|
|
what is the fundamental defect in the dermatosparaxis type of Ehlers-Danlos syndrome?
|
conversion of type I procollagen to collagen
|
|
in what gene is the mutation found in familial hypercholesterolemia?
|
gene encoding the receptor for LDL (involved in the transport and metabolism of cholesterol)
|
|
how highly elevated are the plasma cholesterol levels in familial hypercholesterolemia heterozygotes?
|
two-fold to three-fold
leads to tendinous xanthomas and premature atherosclerosis in adult life |
|
how highly elevated are the plasma cholesterol levels in familial hypercholesterolemia homozygotes?
|
five-fold to six-fold
leads to skin xanthomas, and coronary, cerebral, and peripheral vascular atherosclerosis at an early age myocardial infarction may develop before age 20 |
|
how much of the body's cholesterol circulates in the plasma?
|
7% in the form of LDL
|
|
what are the the lipid components of VLDL particles?
|
rich in triglycerides
lesser amounts of cholesteryl esters |
|
what happens to VLDL particles when they reach capillaries of adipose tissue or muscle?
|
it is cleaved by lipoprotein lipase, a process that extracts most of the triglycerides
|
|
what results from the removal of triglycerides from VLDLs?
|
intermediate-density lipoprotein (IDL) particles
reduced in triglycerides enriched in cholesteryl esters |
|
what two apoproteins are in both VLDLs and IDLs?
|
apoB-100
apoE |
|
what happens to newly formed IDL particles?
|
approximately 50% is rapidly taken up by the liver by receptor-mediated transport
remaining IDL is subjected to further metabolic processing that removes most of the remaining triglycerides and apoprotein E, yielding cholesterol-rich LDL particles |
|
what molecules are recognized by the LDL receptor?
|
apoprotein B-100 and apoprotein E
two molecules contained in IDLs |
|
how are cholesterol-rich LDL particles formed?
|
metabolism of IDL particles that removes most of the remaining triglycerides and apoprotein E
|
|
what is the immediate and major source of plasma LDL?
|
IDL
|
|
what are the two mechanisms for removal of LDL from plasma?
|
LDL receptor on liver cells
scavenger receptor to pick up oxidized LDL |
|
how do LDL surface receptors mediate LDL clearance?
|
LDL binds to cell surface receptors, which are clustered in coated pits
pits containing the receptor-bound LDL are internalized by invagination to form coated vesicles vesicles migrate with the cell to fuse with the lysosomes LDL dissociates from the receptor, which is recycled to the surface apoproteins are hydrolyzed to amino acids, whereas the cholesteryl esters are broken down to free cholesterol |
|
what proteins are required for the exit of cholesterol from lysosomes?
|
NPC1
NPC2 |
|
what processes are affected by the release of intracellular cholesterol?
|
cholesterol suppresses cholesterol synthesis within the cell by inhibiting the activity of HMG CoA reductase
cholesterol activates the enzyme acyl-coenzyme A: cholesterol acyltransferase, favoring esterification and storage of excess cholesterol cholesterol suppresses the synthesis of LDL receptors, thus protecting the cells from excessive accumulation of cholesterol |
|
what is the rate limiting enzyme in the synthetic pathway of cholesterol?
|
HMG CoA reductase
3-hydroxy-3-methylglutaryl coenzyme A reductase |
|
what cells have scavenger receptors for chemically altered (acetylated or oxidized) LDL?
|
monocytes
macrophages |
|
what is the cause of the appearance of xanthomas and premature atherosclerosis?
|
in the face of hypercholesterolemia, there is a marked increase in the scavenger receptor-mediated traffic of LDL cholesterol into the cells of the mononuclear phagocyte system and the vascular wall
|
|
what is a xanthoma?
|
build up of certain fats underneath the surface of the skin
|
|
what are the two special properties of the hydrolytic enzymes in lysosomes?
|
1) function in the acidic milieu of the lysosomes
2) constitute a special category of secretory proteins that are destined not for the extracellular fluids but for intracellular organelles |
|
what happens in the Golgi apparatus to lysosomal enzymes?
|
undergo a variety of post-translational modifications, including the attachment of terminal mannose-6-phosphate groups to some of the oligosaccharide side chains
|
|
what is the function of the terminal mannose-6-phosphate groups on lysosomal enzymes?
|
act as an "address label" that is recognized by specific receptors on the inner surface of the Golgi membrane to insert the lysosomal enzymes into the Golgi membrane
|
|
what are the three general approaches to the treatment of lysosomal storage diseases?
|
enzyme replacement therapy
substrate reduction therapy exogenous competitive inhibitor of the enzyme (paradoxically binds to the mutant enzyme and act as the folding template to assist in proper folding of enzyme) |
|
what is molecular chaperone therapy?
|
use of an exogenous competitive inhibitor of the enzyme (acts as a folding template to assist in proper folding of the lysosomal enzyme)
|
|
what are GM2 gangliosidoses?
|
group of three lysosomal storage disorders caused by an inability to catabolize GM2 gangliosides
|
|
what is required for degradation of GM2 gangliosides?
|
three polypeptides encoded by three distinct genes
|
|
what is the most common form of GM2 gangliosidosis?
|
Tay-Sachs disease
deficiency of hexosaminidase A (alpha subunit) |
|
what is the primary defect in Tay-Sachs disease?
|
severe deficiency of hexosaminidase A (alpha subunit)
|
|
in what population is Tay-Sachs disease especially prevalent?
|
Ashkenazic Jews
|
|
in what tissues do GM2 gangliosides accumulate?
|
heart
liver spleen neurons retina |
|
involvement of what organs dominates the clinical picture in Tay-Sachs disease?
|
neurons in the CNS and ANS
retina |
|
how do neurons in Tay Sachs disease look on microscopic examination?
|
ballooned with cytoplasmic vacuoles, each representing a markedly distended lysosome filled with gangliosides
|
|
what stains for fat are positive in Tay-Sachs disease?
|
oil red O
Sudan Black B |
|
what are the most prominent types of cytoplasmic inclusions in Tay Sachs disease?
|
whorled configurations within lysosomes composed of onion-skin layers of membranes
seen via electron microscope |
|
what is the characteristic finding in the eyes of a patient with Tay Sachs disease?
|
cherry red spot in the macula
represents the accentuation of the normal color of the macular choroid contrasted with the pallor produced by the swollen ganglion cells in the remainder of the retina |
|
what is the cause of the cherry red spot in the eye of patients with Tay Sachs disease?
|
represents the accentuation of the normal color of the macular choroid contrasted with the pallor produced by the swollen ganglion cells in the remainder of the retina
|
|
when do clinical features of Tay Sachs disease manifest?
|
affected infants seem normal at birth, but begin to manifest signs and symptoms at about age 6 months
|
|
what are the presenting symptoms of Tay Sachs disease?
|
motor and mental deterioration
motor incoordination mental obtundation leading to muscular flaccidity, blindness, and increasing dementia cherry red spot in macula complete vegetative state at 1-2 yrs death at 2-3 yrs |
|
what is the effect of most of the mutations that cause Tay Sachs disease?
|
most affect protein folding
|
|
what is the potential treatment type for Tay-Sachs disease?
|
chaperone therapy
|
|
how can antenatal diagnosis and carrier detection of Tay-Sachs disease be performed?
|
enzyme assays
DNA-based analysis |
|
what is the major defect in Sandhoff disease?
|
beta-subunit defect of hexosaminidase A
|
|
what are the three types of GM2 gangliosidoses?
|
Tay-Sachs (hexosaminidase A, alpha subunit)
Sandhoff disease (hexosaminidase A, beta subunit) GM2 activator deficiency |
|
what is accumulated in the lysosomes in Niemann-Pick Disease, Types A and B?
|
sphingomyelin
|
|
what is the deficiency in Niemann-Pick Disease, Types A and B?
|
sphingomyelinase
|
|
what is the difference between Niemann-Pick Disease, Types A and B?
|
type A is a severe infantile form with extensive neurologic involvement, marked visceral accumulations of sphingomyelin, progressive wasting, and early death (in the first 3 years of life)
type B is a less severe form in which patients have organomegaly but generally no CNS involvement |
|
in what population is Niemann-Pick disease predominant?
|
Ashkenazi Jews
|
|
how is the sphingomyelinase gene expressed?
|
preferentially expressed from the maternal chromosome as a result of epigenetic silencing of the paternal gene
|
|
what is seen in the vacuoles found in Niemann-Pick, types A and B?
|
secondary lysosomes that often contain membranous cytoplasmic bodies resembling concentric lamellated myelin figures, sometimes called "zebra" bodies
|
|
where are the lipid-laden phagocytic foam cells distributed?
|
spleen
liver lymph nodes bone marrow tonsils GI tract lungs |
|
what is the effect of splenic involvement in Niemann-Pick disease, types A and B?
|
generally produces massive enlargement
|
|
what is the effect on the brain in Niemann-Pick disease, types A and B?
|
gyri are shrunken
sulci are widened |
|
what is the dominant histologic change in Niemann-Pick disease?
|
vacuolation and ballooning of neurons
|
|
when do the clinical manifestations of type A Niemann-Pick disease present?
|
may be present at birth and almost invariably become evident by age 6 months
|
|
what are the symptoms/presentations of Niemann-Pick disease,types A and B?
|
progressive failure to thrive
vomiting fever generalized lymphadenopathy progressive deterioration of psychomotor function death (usually within the first/second year of life) |
|
what is the most common type of Niemann-Pick disease?
|
Niemann-Pick disease, type C
more common than types A and B together |
|
mutations of what two genes can give rise to Niemann-Pick disease, type C?
|
NPC1
NPC2 |
|
what is the defect in Niemann-Pick disease, type C?
|
primary defect in lipid transport
|
|
what are NPC1 and NPC2 involved in?
|
transport of free cholesterol from the lysosomes to the cytoplasm
|
|
what are the possible clinical presentations of Niemann-Pick disease, type C?
|
hydrops fetalis (stillbirth)
neonatal hepatitis chronic form characterized by progressive neurologic damage |
|
how does the most common form of type C Niemann-Pick disease present?
|
ataxia
vertical supranuclear gaze palsy dystonia dysarthria psychomotor regression |
|
what is the inheritance pattern of Gaucher Disease?
|
autosomal recessive inheritance
|
|
what is the defect in Gaucher Disease?
|
mutation encoding glucocerebrosidase enzyme
normally cleaves the glucose residue from ceramide |
|
what is the most common lysosomal storage disorder?
|
Gaucher Disease
|
|
what is the function of glucocerebrosidase?
|
cleaves the glucose residue from ceramide
|
|
what product accumulates in lysosomes in Gaucher Disease?
|
glucocerebrosides
|
|
what are the primary cells that glucocerebrosides accumulate in in patients with Gaucher Disease?
|
principally in phagocytes
some subtypes in the central nervous system |
|
from what metabolic process is glucocerebroside formed?
|
continually formed from the catabolism of glycolipids derived mainly from the cell membranes of senescent leukocytes and erythrocytes
|
|
what are the causes of pathologic changes in Gaucher disease?
|
burden of storage material
activation of macrophages and the consequent secretion of cytokines (IL-1, IL-6, TNF) |
|
what is the most common clinical subtype of Gaucher disease?
|
type I (chronic, non-neuronopathic form)
storage of glucocerebrosides is limited to the mononuclear phagocytes throughout the body without involving the brain (splenic and skeletal involvements dominate this pattern of the disease) |
|
in what population is Gaucher disease most common?
|
type I - Jewish people of European stock
type II - no predilection for Jews |
|
what is type I Gaucher disease?
|
(chronic, non-neuronopathic form)
storage of glucocerebrosides is limited to the mononuclear phagocytes throughout the body without involving the brain (splenic and skeletal involvements dominate this pattern of the disease) |
|
what is type II Gaucher disease?
|
acute neuronopathic Gaucher disease
infantile acute cerebral pattern virtually no glucocerebrosidase activity in the tissues hepatosplenomegaly, but the clinical picture is dominated by progressive CNS involvement, leading to death at an early age |
|
what is type III Gaucher disease?
|
intermediate between type I and type II
systemic involvement characteristic of type I with CNS disease that usually begins in adolescence or early adulthood |
|
what are Gaucher cells?
|
phagocytic cells distended with glucocerebrosides found in the spleen, liver, bone marrow, lymph nodes, tonsils, thymus, and Peyer's patches in Gaucher disease
|
|
describe the histologic appearance of Gaucher cells
|
rarely appear vacuolated but instead have a fibrillary type of cytoplasm likened to crumpled tissue paper
often enlarged, with one or more dark, ccentrically placed nuclei periodic acid-schiff staining is usually intensely positive |
|
what is seen in the distended lysosomes in Gaucher disease?
|
stored glucocerebroside in stacks of bilayers
|
|
when are Gaucher cells seen in the Virchow-Robin spaces?
|
in Gaucher patients with cerebral involvement
arterioles are surrounded by swollen adventitial cells no storage of lipids in neurons, but neurons appear shriveled and are progressively destroyed |
|
when do signs and symptoms of type I Gaucher disease appear?
|
in adult life
related to splenomegaly or bone involvement |
|
what are the symptoms of type I Gaucher disease?
|
pancytopenia or thrombocytopenia secondary to hypersplenism
pathologic bone fractures and bone pain (if there has been sufficient expansion of the marrow space) |
|
what is the mainstay treatment of Gaucher disease?
|
replacement therapy with recombinant enzymes
|
|
what are the mucopolysaccharidoses?
|
group of closely related syndromes that result from genetically determined deficiencies of lysosomal enzymes involved in the degradation of mucopolysaccharides
|
|
what are mucopolysaccharides?
|
glycosaminoglycans
long-chain complex carbohydrates that are linked with proteins to form proteoglycans |
|
what glycosaminoglycans accumulate in mucopolysaccharidoses?
|
dermatan sulfate
heparan sulfate keratan sulfate chondroitin sulfate |
|
what is the inheritance pattern of mucopolysaccharidoses?
|
all except Hunter syndrome are inherited as autosomal recessive disorders
Hunter syndrome is an X-linked recessive trait |
|
in general, how are mucopolysaccharidoses characterized?
|
coarse facial features
clouding of the cornea joint stiffness mental retardation |
|
in what types of cells are mucopolysaccharides accumulated?
|
mononuclear phagocytes
endothelial cells intimal smooth muscle cells fibroblasts |
|
in what tissues are mucopolysaccharides accumulated?
|
spleen
liver bone marrow lymph nodes blood vessels heart |
|
how do cells affected by mucopolysaccharide accumulation look microscopically?
|
distended with apparent clearing of the cytoplasm to create "balloon cells"
|
|
how do cells affected by mucopolysaccharide accumulation look in the electron microscope?
|
clear cytoplasm can be resolved as numerous minute vacuoles
|
|
what are the common symptoms of mucopolysaccharidoses?
|
hepatosplenomegaly
skeletal deformities valvular lesions subendothelial arterial deposits (particularly in the coronary arteries) lesions in the brain myocardial infarction and cardiac decompensation |
|
what are the important causes of death in mucopolysaccharidoses?
|
myocardial infarction
cardiac decompensation |
|
what is Hurler syndrome?
|
aka mucopolysaccharidosis I-H
deficiency of alpha-1-iduronidase |
|
what is the deficiency in Hurler syndrome?
|
alpha-1-iduronidase
|
|
describe the clinical manifestations of Hurler syndrome
|
affected infants appear normal at birth but develop hepatosplenomegaly by age 6-24 months
growth is retarded develop coarse facial features develop skeletal deformities death occurs by age 6-10 years (CV complications) |
|
what is Hunter syndrome?
|
mucopolysaccharidosis II
X-linked inheritance absence of corneal clouding, and milder clinical course |
|
what is the inheritance pattern of Hurler syndrome?
|
aka mucopolysaccharidosis type I-H
autosomal recessive inheritance |
|
what is the inheritance pattern of Hunter syndrome?
|
aka mucopolysaccharidosis type II
X-linked inheritance |
|
what are glycogenoses?
|
hereditary deficiencies of one of the enzymes involved in the synthesis or sequential degradation of glycogen
|
|
what is the first step in glycogen synthesis?
|
conversion of glucose to glucose-6-phosphate by the action of a hexokinase (glucokinase)
|
|
what is the second step in glycogen synthesis?
|
G6P -(phosphoglucomutase)-> G1P -> uridine diphosphoglucose
|
|
what enzymes elongate the glycogen chain and branches?
|
glycogen synthetases
|
|
what are the major bonds between glucose molecules in glycogen particles?
|
alpha-1,4-glucoside bonds
alpha-1,6-glucoside bonds (branch points) |
|
what enzymes in the liver and muscle split glucose-1-phosphate residues from glycogen?
|
phosphorylases
leaves about four glucose residues on each branch of glycogen molecules |
|
what is limit dextrin?
|
branched oligosaccharide that remains after phosphorylase cleaves glucose from the glycogen molecule
|
|
what enzyme further degrades limit dextrin?
|
debranching enzyme
|
|
what is the enzyme that degrades glycogen in lysosomes?
|
acid maltase
|
|
what are hepatic forms of glycogenoses?
|
inherited deficiency of hepatic enzymes that are involved in glycogen degradation
Sx: storage of glycogen in liver hypoglycemia |
|
what is von Gierke disease?
|
aka type I glycogenosis
deficiency of glucose-6-phosphatase hepatic glycogenosis |
|
what are the hepatic forms of glycogenoses?
|
von Gierke disease
deficiency of liver phosphorylase deficiency of debranching enzyme |
|
what dominates the clinical picture in von Gierke disease?
|
hepatic enlargement
hypoglycemia |
|
what dominates the clinical picture in debranching enzyme deficiency?
|
hepatic enlargement
hypoglycemia |
|
what are the symptoms of the myopathic forms of glycogenoses?
|
muscle cramps after exercise
lactate levels in the blood fail to rise after exercise |
|
what is McArdle disease?
|
aka type V glycogenosis
deficiency of muscle phosphorylase Sx: muscle cramps after exercise serum lactate levels don't rise after exercise |
|
what are the myopathic forms of glycogenoses?
|
McArdle disease (type V glycogenosis)
deficiency of muscle phosphofructokinase (type VII glycogenosis) |
|
with what is deficiency of alpha-glucosidase (acid maltase) associated?
|
glycogen storage in many organs
death in early life lysosomal storage of glycogen (acid maltase is a lysosomal enzyme) |
|
what is Pompe disease?
|
type II glycogenosis
deficiency of alpha-glucosidase (acid maltase) Sx: glycogen storage in many organs death in early life cardiomegaly |
|
with what is deficiency of branching enzyme associated?
|
glycogen storage in many organs
death in early life |
|
what was the first human inborn error of metabolism to be discovered?
|
alkaptonuria (ochronosis)
autosomal recessive deficiency of homogentisic oxidase |
|
what is alkaptonuria?
|
aka ochronosis
autosomal recessive deficiency of homogentisic oxidase Sx: degenerative arthropathy (develops slowly, clinically evident in 30s) not life-threatening, but severely crippling |
|
what is the function of homogentisic oxidase?
|
converts homogentisic acid to methylacetoacetic acid in the tyrosine degradation pathway
|
|
what is the effect of homogentisic acid accumulation in the body?
|
happens in alkaptonuria
a large amount is excreted, imparting a black color to the urine if allowed to stand and undergo oxidation binds to collagen in connective tissues, tendons, and cartilage, imparting to these tissues a blue-black pigmentation |
|
from what do the most serious consequences of ochronosis stem?
|
deposits of the pigment in the articular cartilages of the joints
pigment accumulation causes the cartilage to lose its normal resiliency and become brittle and fibrillated |
|
what joints are attacked in alkaptonuria?
|
particularly intervertebral discs
later the knees, shoulders, and hips may be affected small joints of the hands and feet are usually spared |
|
what are the clinical features of alkaptonuria?
|
degenerative arthropathy develops slowly and usually does not become clinically evident until the 30s
not life threatening, but may be severely crippling |
|
what two types of genes regulate the normal growth and differentiation of cells?
|
proto-oncogenes (promotes cell growth)
tumor suppressor (restrains cell growth) |
|
what is the inheritance pattern of most familial cancers?
|
autosomal dominant
|
|
what normal phenotypic characteristics are governed by multifactorial inheritance?
|
hair color
eye color skin color height intelligence |
|
how many chromosomes are contained in human somatic cells?
|
46 chromosomes
22 homologous pairs of autosomes two sex chromosomes |
|
what is karyotyping?
|
the study of chromosomes
|
|
what is the usual procedure to examine chromosomes?
|
arrest dividing cells in metaphase with mitotic spindle inhibitors (colcemid) and stain the chromosomes
|
|
how are karyotypes obtained?
|
arrange each pair of autosomes according to length, followed by the sex chromosomes
|
|
what is G banding?
|
using a Giemsa stain to ID individual chromosomes on the basis of a distinctive and reliable pattern of alternating light and dark bands
|
|
which arm of a chromosome is designated p?
|
short arm
(p is for petit) |
|
which arm of a chromosome is designated q?
|
long arm
(short arm is p for petit, and q is the next letter in the alphabet) |
|
what is a euploid?
|
any exact multiple of the haploid number
|
|
what is aneuploidy?
|
an error occurring in meiosis or mitosis in which a cell acquires a chromosome complement that is not an exact multiple of 23
|
|
what are the usual causes for aneuploidy?
|
nondisjunction
anaphase lag |
|
what is the result of nondisjunction in gametogenesis?
|
gametes formed will have either an extra chromosome (n + 1) or one less chromosome (n - 1)
|
|
what is anaphase lag?
|
one homologous chromosome in meiosis or one chromatid in mitosis lags behind and is left out of the cell nucleus
result is one normal cell and one cell with monosomy |
|
what generally happens when a monosomic zygote is formed?
|
generally too much genetic information to permit live birth or even embryogenesis
(several autosomal trisomies do permit survival) |
|
what is the only trisomy that doesn't yield severely handicapped infants who almost invariably die at an early age?
|
trisomy 21
|
|
what is mosaicism?
|
two or more populations of cells with different chromosomal complement in the same individual caused by mitotic errors in early development
|
|
what type of mosaicism is most common?
|
mosaicism of the sex chromosome
autosomal mosaicism is much less common |
|
what is the effect of an error in an early mitotic division affecting the autosomes?
|
usually leads to a nonviable mosaic due to autosomal monosomy
|
|
what usually causes structural changes in chromosomes?
|
chromosome breakage followed by loss or rearrangement of material
(occurs spontaneously at a low rate that is increased by exposure to environmental mutagens) |
|
what is a ring chromosome?
|
special form of deletion, produced when a break occurs at both ends of a chromosome with fusion of the damaged ends
|
|
why do ring chromosmes usually cause serious consequences?
|
they do not behave normally in meiosis or mitosis
|
|
what is an inversion?
|
a rearrangement that involves two breaks within a single chromosome with reincorporation of the inverted, intervening segment
|
|
what is a paracentric inversion?
|
an inversion involving only one arm of the chromosome
|
|
what is a pericentric inversion?
|
an inversion with breaks on opposite sides of the centromere
|
|
what is an isochromosome?
|
chromosome consisting of either two short arms or two long arms only
formed when one arm is lost and the remaining arm is duplicated |
|
what is a translocation?
|
a segment of one chromosome is transferred to another
|
|
what is a balanced reciprocal translocation?
|
single breaks in each of two chromosomes, with exchange of material
|
|
what is a robertsonian translocation?
|
aka centric fusion
a translocation between two acrocentric chromosomes, leading two one very large chromosome and one extremely small one (the breaks typically occur close to the centromeres of each chromosome) |
|
what is the most common of the chromosomal disorders?
|
trisomy 21
Down Syndrome |
|
what is the cause of Down Syndrome?
|
trisomy 21
|
|
what is the incidence of trisomy 21 in newborns in the US?
|
1 in 700 newborns
|
|
what is the most common cause of trisomy?
|
meiotic nondisjunction
|
|
what factor has a strong influence on the incidence of trisomy 21?
|
maternal age
1 / 1550 live births in mothers <20 1 / 25 live births in mothers >45 |
|
where does meiotic nondisjunction of chromosome 21 occur in most cases of down syndrome (trisomy 21)?
|
ovum
strong influence of maternal age on incidence of trisomy 21 |
|
how often does the extrachromosomal meterial in Down syndrome derive from the presence of a robertsonian translocation of the long arm of chormosome 21 to another acrocentric chromosome?
|
4% of cases
|
|
how often does Down syndrome result from mosaicism caused by mitotic nondisjunction of chromosome 21 during an early stage of embryogenesis?
|
1% of cases
|
|
what are the diagnostic clinical features of Down syndrome (trisomy 21)?
|
flat facial profile
oblique palpebral fissures epicanthic folds also see: mental retardation abundant neck skin congenital heart defects intestinal stenosis simian crease umbilical hernia predisposition to leukemia hypotonia gap btwn first and second toe |
|
what is the IQ range for 80% of patients with Down syndrome?
|
25 - 50
|
|
how many Down syndrome patients have congenital heart disease?
|
40%
|
|
what are the most common congenital heart defects in Down syndrome patients?
|
ostium primum
atrial septal defects atrioventricular valve malformations ventricular septal defects |
|
what congenital malformations are common in Down syndrome?
|
congenital heart defects
esophageal atresia small bowel atresia |
|
how much is the risk of developing acute leukemia increased in children with Down syndrome (trisomy 21)?
|
10- to 20-fold increased risk of both acute lymphoblastic leukemias and acute myeloid leukemias
|
|
what occurs in virtually all patients with Down syndrome (trisomy 21) older than age 40?
|
neuropathologic changes characteristic of Alzheimer disease
|
|
what is the effect of abnormal immune responses in patients with Down syndrome?
|
predisposition to serious infections, especially of the lungs
predisposition to thyroid autoimmunity |
|
what is the cause of Edwards syndrome?
|
trisomy 18
extra copy of chromosome 18 |
|
what is the cause of patau syndrome?
|
trisomy 13
extra copy of chromosome 13 |
|
what happens in most cases of trisomy 18 and trisomy 13?
|
trisomy 13 - Patau syndrome
trisomy 18 - Edwards syndrome most succumb within a few weeks to months (rarely do these infants survive beyond the first year of life) |
|
what are the symptoms of Edwards syndrome (trisomy 18)?
|
prominent occiput
mental retardation low set ears micrognathia short neck overlapping fingers congenital heart defects renal malformations limited hip abduction rocker-bottom feet |
|
what is the incidence of trisomy 18 (Edwards syndrome)?
|
1 in 8000 births
|
|
what are the symptoms of Patau syndrome (trisomy 13)?
|
microcephaly
mental retardation microphthalmia cleft lip and palate polydactyly cardiac defects umbilical hernia renal defects rocker-bottom feet |
|
what is the incidence of trisomy 13 (Patau syndrome)?
|
1 in 15,000 births
|
|
what is the incidence of chromosome 22q11.2 deletion syndrome?
|
1 in 4000 births
often missed because of variable clinical features |
|
what are the clinical features of chromosome 22q11.2 deletion syndrome?
|
congenital heart defects
abnormalities of the palate facial dysmorphism developmental delay variable degrees of T-cell immunodeficiency variable degrees of hypocalcemia |
|
what two different disorders were previously considered to encompass the clinical features of chromosome 22q11.2 deletion syndrome?
|
DiGeorge syndrome
velocardiofacial syndrome |
|
for what type of illnesses are 22q11.2 deletion syndrome patients at particularly high risk?
|
psychotic illnesses
- schizophrenia - bipolar disorders attention deficit hyperactivity disorder |
|
what is X-inactivation?
|
silencing of one of the X chromosomes in women that occurs at random among all cells in the blastocyst around day 16 of embryonic life
|
|
how can an inactive X chromosome be seen?
|
in the interphase nucleus
darkly staining small mass in contact with the nuclear membrane (Barr body) |
|
given X inactivation during embryogenesis, how are gametes produced in the ovaries?
|
the one X chromosome that is inactivated during embryogenesis is selectively reactivated in oogonia before the first meiotic division
|
|
what is necessary to determine the male sex?
|
regardless of the number of X chromosomes, the presence of a single Y determines the male sex
|
|
what is SRY?
|
sex-determining region of Y gene
gene that dictates testicular development located on the distal short arm of the Y chromosome |
|
what are the features that are common to all sex chromosome disorders?
|
cause subtle, chronic problems relating to sexual development and fertility
often difficult to diagnose at birth (many first recognized at puberty) the higher the number of X chromosomes, the greater the likelihood of mental retardation |
|
what is Klinefelter syndrome?
|
XXY
male hypogonadism that occurs when there are two or more X chromosomes and one or more Y chromosomes |
|
what is the incidence of Klinefelter syndrome (XXY)?
|
1 in 660 live male births
|
|
what are the symptoms of Klinefelter syndrome (XXY)?
|
long legs which create the appearance of an elongated body
small atrophic testes small penis lack of deep voice lack of beard lack of pubic hair gynecomastia |
|
what metabolic problems are commonly seen in Klinefelter syndrome (XXY)?
|
type 2 diabetes
metabolic syndrome |
|
what cardiovascular defect is common in patients with Klinefelter syndrome (XXY)?
|
mitral valve prolapse
|
|
what are the important hormone levels in patients with Klinefelter syndrome (XXY)?
|
elevated FSH
elevated LH low testosterone elevated estradiol |
|
why does Klinefelter syndrome (XXY) cause reduced spermatogenesis and male infertility?
|
testicular tubules are totally atrophied and replaced by pink, hyaline, collagenous ghosts
OR apparently normal testicular tubules are interspersed with atrophic tubules |
|
how do Leydig cells appear in Klinefelter syndrome (XXY)? why?
|
appear prominent
results from atrophy and crowding of tubules and elevation of gonadotropin concentrations |
|
what is Turner syndrome?
|
X
female hypogonadism that is the result of complete or partial monosomy of the X chromosome |
|
what is the most common sex chromosome abnormality in females?
|
Turner syndrome (X)
|
|
what is the incidence of Turner syndrome (X)?
|
1 in 2000 live-born females
|
|
what disorder should immediately be brought to mind when a patient has a cystic hygroma?
|
Turner's syndrome
|
|
how do the most severely affected Turner syndrome patients present?
|
Turner syndrome = X monosomy
most severely affected generally present during infancy with edema of the dorsum of the hand and foot due to lymph stasis, and sometimes swelling of the nape of the neck |
|
what is a cystic hygroma?
|
a congenital multiloculated lymphatic lesion that can arise anywhere, but is classically found in the left posterior triangle of the neck
|
|
what are the principal clinical features of Turner syndrome in the adolescent and adult patients?
|
short stature
low posterior hairline webbing of neck broad chest widely spaced nipples aortic coarctation cubitus valgus streak ovaries infertility amenorrhea pigmented nevi |
|
what is aortic coarctation?
|
a narrowing of part of the aorta (the major artery leading out of the heart)
a birth defect |
|
what is the single most important cause of primary amenorrhea?
|
Turner syndrome
|
|
what immune problems are noted in Turner syndrome patients?
|
approximately 50% of patients develop hypothyroidism as a result of autoantibodies that react with the thyroid gland
|
|
what metabolic problems are noted in Turner syndrome patients?
|
glucose intolerance
obesity insulin resistance (only present in a minority of patients) |
|
what happens to ovaries in Turner syndrome patients?
|
develop normally early in embryogenesis, but the absence of the second X chromosome leads to an accelerated loss of oocytes (complete by 2 years of age)
in a sense, "menopause occurs before menarche," and the ovaries are reduced to atrophic fibrous strands, devoid of ova and follicles (streak ovaries) |
|
define the term "true hermaphrodite"
|
person with the presence of both ovarian and testicular tissue
|
|
define the term "pseudohermaphrodite"
|
person with a disagreement between the phenotypic and gonadal sex
|
|
what is a female pseudohermaphrodite?
|
person with ovaries but male external genitalia
|
|
what is a male pseudohermaphrodite?
|
person with testicular tissue but genitalia that ranges from ambiguous to completely female
|
|
what is the basis of female pseudohermaphroditism?
|
excessive and inappropriate exposure to androgenic steroids during the early part of gestation
|
|
what is the cause of complete androgen insensitivity syndrome?
|
aka testicular feminzation
results from mutations in the gene encoding the androgen receptor |
|
in fragile-X-syndrome, where do the causative trinucleotide expansions occur?
|
oogonia
|
|
in Huntington disease, where do the causative trinucleotide expansions occur?
|
spermatids
|
|
fragile-X-syndrome is a prototype of what kind of diseases?
|
those in which the mutation is characterized by a long repeating sequence of three nucleotides
|
|
what is the second most common genetic cause of mental retardation?
|
fragile-X-syndrome
|
|
what is the inheritance pattern of fragile-X-syndrome?
|
X-linked transmission
|
|
what are the mutations that cause fragile-X-syndrome?
|
inducible cytogenetic abnormality in the X chromosome and an unusual mutation within the familial mental retardation-1 (FMR1) gene
|
|
what are the clinical manifestations of fragile-X-syndrome in males?
|
IQ between 20 and 60
long face with a large mandible large everted ears large testicles hyperextensible joints high arched palate mitral valve prolapse |
|
what is macro-orchidism?
|
large testicles
|
|
what is the most distinctive feature of fragile-X-syndrome?
|
macro-orchidism
present in more than 90% of post-pubertal males |
|
what are normal transmitting males in fragile-X-syndrome?
|
males who are known to carry a fragile-X mutation, but are clinically and cytogenetically normal
(happens in about 20% of males) |
|
what is the incidence of fragile-X-syndrome in females?
|
fragile-X-syndrome is an X-linked disorder, so it is more prominent in males
30-50% of carrier females are affected (i.e. mentally retarded) |
|
what is anticipation with respect to fragile-X-syndrome?
|
clinical features of fragile-X syndrome worsen with each successive generation, as if the mutation becomes increasingly deleterious as it is transmitted from a man to his grandsons and great-grandsons
|
|
how is anticipation explained?
|
during the process of oogenesis, but not spermatogenesis, premutations (expansions of 55-200 CGG repeats) can be converted to mutations (expansions of 200-4000 CGG repeats) by triplet repeat amplification
|
|
what is a feature that is unique to mitochondrial DNA? why?
|
it is inherited from the mother only
ova contain numerous mitochondria within their abundant cytoplasm, whereas spermatazoa contain only a few, if any |
|
how many genes are contained in mitochondrial DNA?
|
37
(22 are transcribed into tRNAs and 2 are transcribed into rRNAs) |
|
what DNA encodes enzymes involved in oxidative phosphorylation?
|
mitochondrial DNA (mtDNA)
|
|
what organs are mostly affected by mutations in mtDNA? why?
|
CNS
skeletal muscle cardiac muscle liver kidneys these organs are most dependent on oxidative phosphorylation (mtDNA encodes the enzymes involved in oxidative phosphorylation) |
|
what is heteroplasmy?
|
the presence of a mixture of more than one type of an organellar genome (mitochondrial DNA (mtDNA) or plastid DNA) within a cell or individual
|
|
what is the threshold effect with respect to mitochondrial DNA?
|
since most eukaryotic cells contain many hundreds of mitochondria with hundreds of copies of mtDNA, it is possible and indeed very frequent for mutations to affect only some of the copies, while the remaining ones are unaffected
a minimum number of mutant mtDNA must be present in a cell or tissue before oxidative dysfunction gives rise to disease the "threshold" is reached most easily in metabolically active tissues (CNS, skeletal muscle, cardiac muscle, liver, and kidneys) |
|
what is a prototype disorder of diseases associated with mitochondrial inheritance?
|
Leber hereditary optic neuropathy
|
|
what is the inheritance pattern of Leber hereditary optic neuropathy?
|
mitochondrial inheritance
this is a neurodegenerative disease that is caused by mutations in mitochondrial DNA (responsible for ox-phos enzymes) |
|
what is Leber hereditary optic neuropathy?
|
neurodegenerative disease that manifests as a progressive bilateral loss of central vision (impairment is first noted btwn ages 15 and 35)
caused by mutations in mitochondrial DNA (responsible for ox-phos enzymes) |
|
what is imprinting?
|
selective inactivation of either a maternal or paternal allele
|
|
what is maternal imprinting?
|
transcriptional silencing of the maternal allele
|
|
what is paternal imprinting?
|
transcriptional silencing of the paternal allele
|
|
where does imprinting occur?
|
occurs in the ovum or the sperm, before fertilization, and then is stably transmitted to all somatic cells through mitosis
|
|
how are imprinted genes found?
|
can occur in isolation
more commonly they are found in groups that are regulated by common cis-acting elements called imprinting control regions |
|
what are the clinical characteristics of Prader-Willi syndrome?
|
mental retardation
short stature hypotonia profound hyperphagia obesity small hands and feet hypogonadism |
|
what are the clinical characteristics of Angelman syndrome?
|
mental retardation
ataxic gait seizures inappropriate laughter |
|
what causes Prader-Willi syndrome?
|
deletion of a portion of paternally derived chromosome 15
(same portion as in Angelman) |
|
what causes Angelman syndrome?
|
deletion of a portion of maternally derived chromosome 15
(same portion as in Prader-Willi) |
|
patients afflicted with what illness are sometimes referred to as "happy puppets"? why?
|
Angelman syndrome (deletion of a portion of maternal chromosome 15)
these patients characteristically present with ataxia and inappropriate laughter |
|
what is uniparental disomy?
|
inheritance of both chromosomes of a pair from one parent
|
|
what is the affected gene in Angelman syndrome?
|
a ubiquitin ligase that is involved in catalyzing the transfer of activated ubiquitin to target protein substrates
|
|
what gene is affected in Prader-Willi syndrome?
|
no single gene has been implicated, but one that is included is a gene that encodes small nuclear riboprotein N (controls gene splicing; expressed highly in the brain and heart)
|
|
what is the function of small nuclear riboprotein N?
|
controls gene splicing
(expressed highly in the brain and heart) |
|
what are the two imprinting illnesses?
|
Prader-Willi syndrome
Angelman syndrome both are caused by a deletion of the same portion of chromosome 15 (Prader-Willi if the deletion affects the paternally derived chromosome 15; Angelman syndrome if the deletion affects the maternally derived chromosome 15) |
|
what are repeat-length polymorphisms?
|
short repetitive sequences of DNA that are repeated a variable number of times in different people
|
|
what are the two types of repeat-length polymorphisms?
|
microsatellite repeats (<1 kilobase; repeat size of 2-6 base pairs)
minisatellite repeats (larger; 1-3 kilobase; repeat size of 15-70 base pairs) |
|
what stretches of DNA can be used to establish genetic identity for linkage analysis?
|
microsatellites and minisatellites (repeat-length polymorphisms)
they are extremely variable within a given population |
|
what type of assays have been extensively validated and are now routinely used for determining paternity and for criminal investigations?
|
panels of microsatellite marker PCR assays
|
|
what is a southern blot?
|
using a DNA probe to identify a specific sequence of genomic DNA
|
|
what is FISH?
|
fluorescence in Situ Hybridization
uses DNA probes that recognize sequences specific to particular chromosomal regions |
|
define epigenetics
|
the study of heritable chemical modifications of DNA or chromatin that does not alter the DNA sequence itself
ex. methylation and acetylation of histones |