X-linked inheritance XD, XR Flashcards
Heterogametic
Y from father,X from mother XY
Pseudoautosomal region
region of homology b/w X and Y chromosomes exists at the tip of their short arms.
In males, prophase I, homologous pairing b/w X and Y chromosomes occurs at pseudoautosomal segments
Holandric Inheritance
Y-linked genes are transmitted from father to son.
Genes on sex chromosomes
X chromosomesd~500 genes, Y~fewer genes known, SRY close to pseudoautosomal region, H-Y histocompatibility antigen-gene for hairy ear and genes involved in spermatogenesis
Males are always . . . .
HEMIZYGOUS. never homozygous or heterozygous
Dosage compensation
females with XX and males with XY, EXPRESS X-LINKED GENES ESSENTIALLY AT THE SAME LEVEL
Lyon’s Hypothesis
explains disparity b/w gene dosage and the level of expression of X-linked genes: Only 1 X is transcriptionally active, inactive X is a Barr Body/Sex chromatin. Inactivation occurs early in embryonic life and random and permanent. . . thereafter the same X is inactivated in all daughter cells
X Chromosome inactivation
Achieved by methylation of CpG dinucleotides in the promoter regions. X inactivation is incomplete: 3 classes of genes escape inactivation
Genes at and outside psuedoautosomal region. E.g. steroid sulfates-> plasma level high in females (deficiency->Icthyosis:fish-like scaley skin
X Non-random inactivation
when karyotype involves a structurally abn X:deletions, duplications, and isochromosome, the ABN X will be inactivated.
Cells prefer to keep the autosomal gene active
Manifesting heterozygotes
mutated allele is present on active X on all or most cells
Asymptomatic heterozygotes
mutant allele preferentially on inactive X in most or all cells
EX:color blindess, hemophilia A and B, DMD,Wiskott-aldrich syndrome (immunodeficiency)
X-linked recessive inheritance
phenotype more frequent in males, man transmits gene to ALL daughters, NOT transmitted from father to son. Can be transmitted through female carriers for generations.
May be CONSANGUINITY.
Sig proportion are new mutations (DMD)
X-linked Recessive and males.
No male-to-male transmission! males are more affected b/c they are homozygous.
X-R: Mutation? Characteristics? Duchenne’s muscular dystrophy (DMD)
Dystrophin gene, frame-shift deletions. Onset 3-5 yrs, wheelchair bound by 12 yrs.
Dystrophin protein maintains sarcolemmal stability.
Musculare degeneration, pseudohypertrophy, death in 20s due to respiratory insufficiency
X-D: Mutation? Characteristics? Fragile X syndrome
CGG at 5’ UT region.
Defect in FMR-1 transcription-hypermethylation and silencing.
Mental retardation, oversized jaws and ears, enlarged testes, temper tantrums.
X-R: Mutation? Characteristics? Hemophilia A
Mutation in Factor VIII
Uncontrolled bleeding.
Both factor 8 and 9 are required for activation of factor X in intrinsic coagulation path.
Males predominantly affected
X-R: Mutation? Characteristics? Hemophilia B
Mutation in Factor IX
Uncontrolled bleeding
X-R: Hemophiliia A and B
Sxs depend on degree of deficiency.
NEONATAL BLEEDING-> intracranial hemorrhage, severe hematoma, prolonged bleeding from cord or umbilical area.
SOFT-TUSSUE HEMORRHAGE-trauma related
HEMARTHROSIS-bleeding into joints
HEMATOMA formation after mild trauma, bruise easily
PROLONGED PARTIAL THROMBOPLASTIN TIME(PPT-intrinsic)
Normal PT-extrinsic pathway
X-linked Dominant inheritance
regularly expressed in heterozygotes.
Affected males(with normal mates) have:
~all daughters affected, No sons affected.
Hemizygous males are generally more severely affected.
No male-to-male transmission.
both male and female offspring have 50% chance of inheriting the phenotype
X-linked Dominant inheritance: IF THE FATHER IS AFFECTED
if the father affected, the mutant allele always goes to the daughter.
All the sons of affected fathers will be normal.
X-linked Dominant inheritance: IF THE MOTHER IS AFFECTED
If mutant allele is in mother, there is an equal chance for the sons +daughters to get it.
X-linked Dom Disorders: Resistant Rickets
Rickets despite adequate Vit. D.
Characterized by LOW PLASMA AND HIGH URINARY PHOSPHATE LEVELS.
due to IMPAIRED ABILITY OF KIDNEY TUBULES TO REABSORB FILTERED PHOSPHATE->X-LINKED HYPOPHOSPHATEMIC RICKETS.
females usually less severe skeletal changes than males.
X-linked Dom Disorders: Ornithine Transcarbamoylase (OTC) deficiency
UREA CYCLE ENZYME->absent->LETHAL NEONATAL.
HYPERAMMONIEMIA in affected males.
heterozygous females exhibit wide variation on OTC levels and clinical severity.
INCOMPLETELY DOMINANT-X-LINKED DISORDER
X-linked Dom Disorders: Lethal in males: Rett Syndrome
RETT SYNDROME-mental disorder that appears to be PRENATAL LETHAL IN HEMIZYGOUS MALES, AND PRECLUDE REPRODUCTION IN AFFECTED FEMALES.
occurs exclusively in females, who are the only cases in the families. (males die early) Considered to be new mutations.
X-linked Dom Disorders: Lethal in males: Incontinentia Pigmenti 2
lethal in hemizygous males:microcephaly, small/absent teeth, loss of hair, swirling skin rash,erythema, vesicles, mental retardation.
Female heterozygotes->totally nonrandom X-inactivation->X chromes carrying IP2 mutant are inactive.
Genetic Heterogeneity
Includes a number of phenotypes that are similar, but different genotypes at different loci.
