Week 4 Flashcards
inactived X chromosomes, seen in Kleinfelter syndrome
Barr bodies
normal phenomenon where one of the 2 X chromosomes in every cell of a female individual is inactivated during embryonic development
lionization
what percent of women have X inactivation ration
90%
Why is the normal X chromosome inactivated in balanced X autosome translocation?
inactivation of X chromosome causes an imbalance of gene expression
Sons of an affected male are usually unaffected in ____, while daughters are obligate carriers
X linked inheritance
expressed in all males who receive mutation, can skip generation, no father to son transmission
X linked recessive
CCG triplet expansion in 5’ FMR1 (gene not expressed), 56-200 repeats= unstable mutation, promoter silencing by CpG methylation= no FMR1 expression
anticipation DNA methylation and haplotype effect (arrangement of neighboring loci on the same chromosome)
Fragile X (XD with reduced penetrance)
mutation in MECP2 gene (Xq28, methyl-CpG-binding protein-2), transcriptional silencing, and epigenetic regulation of methylated DNA
95% de novo mutations, almost exclusively in male germline
manifests after 6-18 months of age in females, men die in utero or after birth
Impairments in language and coordination and repetitive hand movements like wringing/squeezing or clapping/tapping, slower growth, difficulty walking, smaller head size, seizures, scoliosis, and sleeping problems
variable expressivity
Rett syndrome (XD)
mutation in F8 (Type A) and F9 (Type B)
most cases of severe type A due to intron 22 inversion results in 2 incomplete transcripts
acute and recurrent hemarthrosis (bleeding into joints) and hematomas
with age, severity, and frequency of episodes increase
bleeds in brain are life-threatening
F9 expression increases by 1/3 at puberty
Hemophilia A and B (XR)
X linked recessive + X inactivation:
Mutation in dystrophine gene
Large deletions (60-65%), large duplications (5-10%), small deletions, insertions, or nucleotide changes (25-30%)
33% de novo mutations
14% germline mosaicism → 7% reccurerence risk in apparent noncarrier mothers with affected child
Progressive degeneration of skeletal muscle, usually after a latency period of seemingly normal development and function (>2 yrs), difficulty in climbing stairs, frequent falls, and progressive difficulty in rising from floor are early features. Pseudohypertrophy of calves, mild mental retardation, cardiomyopathy (95%), 50-60% carrier females have cardiac abnormalities, and slightly elevated serum CK levels even in absence of other symptoms
Duschene Muscular Dystrophy
X linked recessive
Mucopolysaccharidosis type II (MPS II), accumulation of glycosamingoglyicas (GAGs) in lysosome
Mutation is IDS= iduronate-2-sulfatase
break down of 2 ECM proteoglyvans, dematan sulfate and herpan sulfate is impared
Born normal then, abdominal hernias, ear infection, runny noses, colds, coarseness of facial features, prominent forehead, nose with flattened bridge, an enlarged tongue, large head, hepatosplenomegaly, aggressive behavior
Hunter Syndrome (XR)
X linked recessive
Mutation in Bruton tyrosine kinase (BTK), stops B-cell maturation at pre-B cell stage. T cell immunity remains in tact
No antibodies in blood, newborns normal, present w/ lung infections, ear infections, pink eye, and sinus infection. Infections that cause diarrhea, Note: live attenuated vaccines could be dangerous because of no immune response (live polio, MMR)
Bruton Agammaglobulinemia
(aka X Linked agammaglobinulinemia XLA)
X linked recessive
Incomplete penetrance in heterozygous female because random x inactivation
Mutation in a-galactosidase A → accumulation of glycolipid globotriaosylceramide in walls of blood vessels
Multisystem disorder (kidneys, heart, NS, skin, eyes), full body or localized pain to extremities (deposits in nerve fibers) or GI tract, angiokeratomas, proteinuria, kidney failure, cardiac hypertrophy, valve disease, anhidrosis, corneal clouding
Fabry Disease
X linked recessive
Deficiency in HGPRT 1, overproduction of uric acid (hyperuricema)
Failure of purine salvage pathway = accumulation of breakdown product and stimulation of de novo synthesis pathway
Sand like crystals of uric acid in diapers, gout, kidney stones, bladder, ureter, hypotonia, aggressiveness, finger biting, patients poorly use vitamin B12 → megaloblastic anemia, death usually due to kidney failure or complications from hypotonia
Lesch Nyhan Syndrome
X linked recessive
Mutation in GPR143 (OA1) product GPCR like protein localizes to melanosomes and involved in melanosomal biogenesis. Activation of OA1 receptor by L-DOPA → secretion of neurotropic factor by retinal pigment epithelium helps in normal retinal development
Reduced coloring of iris and retina (ocular hypopigementation, eye appears blueish pink); foveal hypoplasia, rapid involuntary eye movement (nystagmus), poor vision and depth perception, increased sensitivity to light
Astigmatism and lazy eye/strabismus
Ocular Albinism
X linked recessive
OTC deficiency, failure to convert carbon phosphate to citrulline, most common urea cycle disorder → hyperammonemia
Male infant by the second day of life becomes irritable, lethargic, stops feeding, poorly controlled body temperature and respiratory rates, may experience seizures, metabolic encephalopathy develops, and can progress to coma and death within the first week of life
Treatment goal = reduce periods of hyperammonemia
*Gene therapy
Ornithine transcarbamylase deficiency
X linked recessive
Mutation in WAS gene, can also cause X linked thrombocytopenia (XLT), mainly expresses in hematopoietic cells, nucleation promoting factor (NPF) for Arp2/3 complex (binds actin)
Mucrothrombocytes were observed only else in ARPC1B deficiency
Immune deficiency, Thrombocytopenia (low platelet count), Eczema, Recurrent infections, bloody diarrhea,
First signs- petechiae and bruising
Serum IgM low (IgG normal)
Spontaneous nose bleeds and blood diarrhea
Increased risk of leukemia and lymphoma
Wiskott Aldrich Syndrome
X linked recessive
G6PD deficiency, only enzyme in erythrocytes that supplies NADPH , depletion → oxidation of Hb, RBC turnover, production of bilirubin and jaundice
Yellow skin, dark urine, shortness of breath, fatigue, hemoglobinuria, acte hemolytic anemia, acute kidney failure. Anemia and jaundice in newborns, pale, extreme tired, tachycardia, dyspnea, splenomegaly
Triggers: infection, medication (aspirin or antimalaria quinin), stress of fava beans (favism)
G6PD deficiency
When homozygotes have more severe phenotypes than heterozygotes or compound heterozygotes, almost all disease with dominant inheritance are in this group
incomplete dominance
when you have similar phenotype in homozygotes, heterozygotes, and compound heterozygotes
pure dominant
disease manifests most often when both alleles are mutated (homozygotes or compound heterozygotes), assuming no mosaicism
autosomal recessive
when a person has 2 or more genetically different sets of cells in his or her body
mosaicism
if case is not isolated, others affected are usually in same sibship (not observed by parents, offspring, or other relatives) because of low probability, males and females typically equally effected, parents typically asymptomatic, parents may be consanguineous
autosomal recessive
most molecular basis of recessive disorders involves enzyme deficiencies:
inborn errors of metabolism
allelic variation may have little to no effect on enzyme activity
polymorphism
effects of reduced enzyme activity
- accumulation of substrate
- deficiency of product
- new (toxic) product/alternate pathway
AR
VARIABLE EXPRESSIVITY
Genetic and environmental modifiers
Most common fatal AR in white populations
CFTR gene (most common F508 deletion - 70%)
Exocrine pancreatic insufficiency, obstructive azoospermia (no sperm- 95% bc bilateral absence of vas deferens), elevate sweat Cl-, growth failure, meconium elius, idiopathic chronic pancreatitis but some lack clinical signs= partial phenotype
Cystic fibrosis
AR
HETEROZYGOUS ADVANTAGE, novel property mutation, compound heterozygosity, ethnic variation
B- globin (HBB) Glu6Val mutation decreases solubility of deoxy Hb → form gelatinous network of stiff fibrous polymers that distort RBC → sickle shape
Sickled erythrocytes occlude capillaries → infarction
Anemia, functional asplenia (inc susceptibility to bacterial infections= major cause of death), failure to thrive, splenomegaly, repeated infections, and dactylitis (painful swelling of hands/feet from occlusion of capillaries, child won’t want to stand),
Newborn screening- initiate antibiotic prophylaxis through age 5
higher level of Hb Fetal associated with lower morbidity and mortality
BCL11A gene- TF that silences gamma-globin expression, silencing can increase HbF (HBG) expression
MYB- TF silences HBG. trisomy 13- high HbF bc miR-15a and miR16-1 target MYB encoded on chromosome 13
Sickle Cell Anemia
AR
Mutation in ATP7B gene- 90% (transports excess Cu2+ into bile, excreted in waste products)
Cu2+ metabolism (needed for cytochrome c oxidase/ complex IV and other enzymes) Cu2+ accumulates in liver, brain, and eye
Kayser-Fleischer rings in cornea, low serum caeruplasmin (Cu2+ transport protein), Cu2+ accumulates in liver → hepatitis and cirrhosis and in basal ganglia (brain) → severe progressive neurological disability
Vomiting, weakness, fluid build up in abdomen, swelling of legs, yellow skin, itchiness, tremors, muscle stiffness trouble speaking, personality changes, anxiety, psychosis
Wilson’s Disease
AR
Heterozygote advantage (malaria)
Defect/deletion in a-chains of Hb, excess B- chains → nonfunctional B4 tetramers= HbH, precipitate and forms inclusions → removal in spleen and anemia
Infants w/ severe type and high levels of Hb Bart’s (gamma 4) suffer severe intrauterine hypoxia and massive fluid accumulation= hydrops fetalis
Treatment: transfusion (iron overload), bone marrow transplant, gene therapy, hypoxyurea and thalidomide (to induce HbF)
More a-chains lost → inc severity of disease
A-thalassemia
AR
Reduces (B+) or absent (B°) synthesis of b-globin chains of Hb tetramer
B chain imp only in postnatal period= later onset
Point mutations (not deletions)
A- thalassemia genes are modifiers for B-thalassemia
Hypochromic, microcytic anemia and an imbalance in globin synthesis due to excess a- chains which precipitate (Heinz bodies)
B-thalassemia
AR
Mutation in dynein arms, DNAH5 and DNAl1
80% full term infants present w/ respiratory distress within 24hr of birth, productive “wet” cough begin under 6mo, chronic airway infection, inflammation, progressive obstruction, bronchiectasia (widening of airways), 50% situs inversus totalis (flipped organs), infertility due to sperm and cilial immotility
Kartagener Syndrome
Aka Primary Ciliary Dyskinesia (PCD)
AR
Most compound heterozygotes
Mutations in PKHD1, protein polycystin/polyductin (or fibrocystin/polyductin, FPC)
FPC- present in primary cilia of renal tubules and intrahepatic bile ducts
Abdominal discomfort, abdominal mass, polyuria, polydipsia, hypertension with progression to end stage kidney disease by age 15, small # live longer, but have liver dysfn
Autosomal Recessive Polycystic Kidney Disease (ARPKD)
AR
Lysosomal storage disease, ethnic variation, genetic drift (Ashkenazi jews), pseudodeficency, population screening
Defect in hexosaminidase (Hex A; GM2→ GM3)
Age at onset: infancy through adulthood
Infants normal til 3-6 mo, then progressive neurological deterioration and loss of motor skills (turning over, sitting, crawling), seizures, vision, and hearing loss, paralysis, cherry red spot on retina (neuronal death), neurodegeneration underlying cause of death at 2-4 yrs
Tay-Sachs Disease
AR
Mutation in acid alpha glucosidase (accumulation of glycogen in lysosomes) usually glycogen taken up with autophagy
Progressive muscle weakness (myopathy), born normal, by 3 mo feeding and swallowing problemsn, macroglossia, respiratory difficulties and infections, muscle weakness (floppy baby), hypotonia, hypertrophic cardiomyopathy, die by 2 years
Pompe Disease
Aka glycogen storage disease type II/ floppy baby syndrome
AR
Allele heterogeneity
alpha-L-idurondase defect (breaks down unsulfated a-L-iduronic acid found in dermatan sulfate and heparan sulfate- ECM proteoglycans)
Mucopolysaccharidosis type IH (MPSIH) accumulation of glycosamingoglycans (GAGs) in lysosome
Coarsening of facial features, large head with prominent frontal bones, elongates skill, corneal clouding, hearing impairment, hepato- cardio- splenomgaly, umbilical hernia, skeletal abnormalities, lips large, hold jaw open
Life expectancy ~9 yr, bone marrow transplant helps increase survival
Hurler Syndrome
AR
Allele heterogeneity
OCA1-deficiency (absence) of enzyme for melanin (tryosinase)
OCA2-defect in the P protein
OCA3- mutation in tyrosinase related proteins
Complete lack or severe reduction of melanin → hypopigmentation of hair, skin, and eyes,
Photosensitivity and reduced visual acuity w/ OCA1- deficiency (most severe)
Oculocutaneous albinism
Describes the inheritance where homologous regions at tips of X and Y chromosomes do meiotic recombination which ALLOWS FOR MALE-TO-MALE TRANSMISSION
pseudoautosomal inheritance
homologous regions at tips of X and Y chromosomes ____; genetic loci located in these regions are called ____
pseudoautosomal regions
pseduoautosomal loci
Dominant
Affects mainly females
SHOX gene mutation
Disproportionate short stature, mesomelic shortening of limbs, bowing of tibia, increased muscle size, deformity of forearms
Leri Weill Dyschondrosteosis
male limited precocious puberty meaning only males affected because mutation in luteinizing hormone receptor –> (+) of LHR even without ligand, premature growth spurt, FATHER TO SON TRANSMISSION distinguishes from X linked, mutation in LCGR gene encoding leutenzing hormone receptor
sex-limited AD inheritance
Y linked inheritance
(father to son transmission)
Deletion in AZF (azoospermia factor), region of Y chromosome
Mutation in USP9Y
Azoospermina (no mature sperm), oligospermia (low sperm count),
Y chromosome infertility
Y linked inheritance
(father to son transmission)
Mutation in SRY (sex determining region Y)
46, XY w/ female external genitalia
No ovaries (“streak gonads”), gonadectomy to prevent gonadoblastoma, hormone replacement therapy to induce menstruation, can become pregnant w/ donated eggs or embryo, no estrogen, breast, or ovaries
Swyer Syndrome
transmitted through maternal germline, smaller, circular DNA, homoplasy and heteroplasmy (DNA copies are identical, DNA variant copies), replicative segregation (cell division), disease threshold
Multiple organs affected esp those w/ high energy demands- nerve, muscle, kidneys
Mitochondrial inheritance
why does mitochondria need its own translational apparatus?
because genes in mtDNA are using genetic code which is different than that used in nucleus
all children of homoplasmic females- WILL inherit mutation
all children on homoplasmic OR heteroplasmic males- WILL NOT inherit mutation
all children of heteroplasmic females- WILL inherit mutation, but not heteroplasmy level
mitochondrial inheritance
heteroplasmic deletions not heritable, pleiotropy, variable expressivity, variability in mutation loads btw tissue, father will not have affected children
mitochondrial inheritance
Mitochondrial inheritance
Reduced penetrance in females (more males affected
11778 G → A (transition) mutation in MT-ND6 (complex I)
Degeneration of retinal ganglion cells (RGCs) and axons, acute or subacute central vision loss, tobacco and alcohol risk factors, color vision affected visual acuity may improve
Leber’s hereditary optic neuropathy (LHON)
Mitochondrial inheritance
3243 A → G (transition) mutation in MT-TL1
Difficulty understanding/thinking, temporary muscle weakness or paralysis (hemiparesis), seizures, hallucinations
Inc in lactic acidosis- vomiting, abdominal pain, fatigue, muscle weakness
Stroke like- weakness/paralysis of an arm or leg or side of body, slurred speech, problems thinking of or saying right word
MELAS
(mitochondrial encephalomyopathy, lactic acidosis, and stroke like episodes)
not inherited, unstable expansion within affected gene of a segment of DNA consisting of repeating subunits of 3 or more nucleotides in tandem (CAG –> CAGCAGCAGCAG), both germline and tissue specific somatic instability, replication, repair, and recombination contribute to instability,
ANTICIPATION
disease occurs when number of repeats exceeds some threshold (ex Huntington’s)
Dynamic mutation
disease manifests itself at earlier age as it moves through subsequent family generations –> more severe symptoms
anticipation
AD
ANTICIPATION
Parental transmission bias from father (more severe)
CAG (glutamine) repeat expansion in HTT gene (HD gene), stretch of Glu residues sequesters TFs → TFs not available → gene expression affected
Jerky, random, uncontrollable movements=chorea, rigidity, abnormal posture and facial expression, ⅓ psychiatric abnormalities, ⅔ cognitive and motor abnormalities
Huntington Disease
how do we get increased number of repeats in Huntington’s diseases when transmitted through germline
when CAG repeats gets replicated, the DNA strand may slip back by 3 nucleotides or more and increase number of repeats
X linked dominate
Mainly men affected
Somatic mosaicism
ANTICIPATION
Most commonly inherited causing intellectual disability
CGG triplet repeat expansion in 5’ FMR1 gene,
200-1000 repeats= affected , 56-200 repeats= “unstable mutation” (inc risk in next generation)
Promoter silencing by CpG methylation- no FMR1 expression
Post puberty- long face w/ prominent jaw and forehead, large ears, macroorchidism, repeat length mosaicism and methylation determines severity
Fragile X Syndrome
AD
1 in 500 Quebec
CTG expansion in 3’ untranslated region of DM1 protein kinase (DMPK1), OR CCTG repeat expansion in intron of CNB gene
DM1 is spliceopathy (abnormal splicing of genes) (CCG serves to bind splicing factors)
Muscle weakness, cataracts, mytonia, “warm up phenomenon”, appears more pronounced after rest and improves w/ muscle activity. Distal muscle weakness, impairment of fine motor tasks, myopathic face or “hatchet face”
Myotonic Muscular Dystrophy
AR
GAA expansion in Frataxin (FXN), involved in iron handling and Fe-S cluster biogenesis (esp in mitochondria)
Gene silencing due to abnormal repeats
Difficulty walking and poor balance (ataxia), loss of sensation in arms and legs, impaired speech (dysarthria), scoliosis, primary cause of death= cardiomyopathy
Friedreich Ataxia
Centromere in middle, arms same length
metacentric
centromere shifted towards telomere
submetacentric
chromsomes 13,14,15,21,22, involved in urban translocation, centromere moved to very extreme of one of the arms
acrocentric
Most prominent cause of chromosomal abnormality disorders
Nondisjunction
abnormal chromosome segregation
when chromosome number does not equal 46
heteroploid
chromosomal number = n x 23 (23, 46, 69, 92), covers both normal and abnormal
euploid
23 chromosomes (gametes only)
haploid
46 chromosomes (normal)
diploid
69 chromsomes, can be liveborn
triploid
92 chromosomes, fetuses are always spontaneously aborted
tetraploid
not euploid, any number of chromosomes, ex) Trisomy 13, 18, 21
ex) XXX syndrome and Klinefelter syndrome (XXY)
aneuploid
arises from meiotic nondisjunction or failure of chromosomes to separate in 1 out of 2 divisions of meiosis, 2 chromosomes in same
nondisjuction
arises from meiotic nondisjunction or failure of chromosomes to separate in 1 out of 2 divisions of meiosis, 2 chromosomes in same
nondisjunction
the genome has the normal complement of chromosomal material, 1 in 500, often no phenotype, can interrupt genes reciprocal and non-reciprocal translocation, inversions, or require alternate segregation in meiosis, alternate segregation
balanced rearrangement
some material is either added or missing in genome, can be stable or unstable, adjacent segregation, less frequent, partial trisomy (duplication), partial monosomy (deletion, more harmful), marker chromosomes (supernumerary)
unbalanced
most common type of translocation, reciprocal, 2 acrocentric chromosomes that fuse near centromere region w/ loss of short arms, often pseudodicentric (centromere inactivated)
chromosomal deletions or addition result in syndromes of multiple malformations, including trisomy 13 (Patau syndrome) and trisomy 21 (Down syndrome).
Robertsonian translocation
Can be paracentric (happens in one chromosomal arm) or pericentric (around centromere), fetuses with unbalanced chromosomes from meiosis of paracentric are not viable
inversions
What is the similarity and difference between Robertsonian and isochromosomes?
Robertsonian- form of translocation where 2 acrocentric chromosomes fuse at centric ends, forms one large metacentric chromosome and one small fragment, leads to Trisomy 13 and 21
Isochromosomes- made of mirror images of one arms of chromosomes, partial trisomy in isochrome and partial monosomy in lost arm, happens in X chromosome and acrocentric, leads to Turner syndrome
range of signs and symptoms that can occur in different people with same genetic condition ex) cystic fibrosis
variable expressivity
both alleles of a gene are partially expressed, resulting in an intermediate or different phenotype, most dominant diseases ex) achondroplasia
incomplete dominance