9: Sex-Linked Disorders Flashcards
Lyonization
X Chromosome Inactivation
Sex-Linked Inheritance
Genes on X and Y chromosomes
X chromosome 5% of human genome
Y chromosome only a few genes
Male hemizygosity (males express all genes on X) X-chromosome inactivation: only one X needed, dosage compensation reducing expression to one allele, variety in female presentation
Sex-limited traits (don’t confuse with)
Traits limited to expression in one sex though genes in both sexes
(Milk production and cryptorchidism)
Sex-influenced (don’t confused with)
Expression of traits influenced by sex hormones
Male pattern baldness
Pseudoautosomal Region
X and Y have regions, at telomeres, that function like any other chromosome
-genes here need biallelic expression (prevents males from having Turner syndrome phenotype)
- crossing over between genes here
- Not turned off in females
X Chromosome Inactivation
Xist involved
Random from cell to cell (50/50)
If mutant on one X, can result in variable phenotype and disease expression
-X-linked recessive diseases more severe in males, but can be expressed in females to varying degrees.
X-Chromosome Inactivation (molecular)
of X chromosome-1= Barr Bodies
Zygote-divides-one of the chromosomes will get inactivated (heterochromatin, acetylation and methylation)=Barr Body
Mosaic as end result (different tiles of X expression)
Ends stay active regardless
Females are mosaics for genes on X chromosome
Starts early in germline; undo all of this when female gives egg
Tortiseshell Cat
Example of X-Chromosome Inactivation
Different colors on fur
Hypohidrotic Ectodermal Dysplasia (X-Chromosome Inactivation)
Females can be missing a few teeth or have patches of anhidrosis (mosaic)
Males may have no teeth, anhidrosis and sparse hair
Y Chromosome
Testicular Development by SRY
Spermatogenesis-Yq genes
Used to trace male migration, forensics, paternity testing
Sex-Linked Genetic Disorders (basic)
All are X-linked, usually recessive
Mutated Y genes produce infertility and not passed on
Sex-Linked Genetic Disorders (recurrence risk)
Affected male, 100% daughters will be carriers, 100% sons unaffected
Carrier female, 50% sons affected, 50% daughters will be carriers
Sex-Linked Inheritance Examples
Hypohidrotic ectodermal dysplasia
Incontinentia pigmenti
Duchenne muscular dystrophy
Hemophilia A and B
Red/Green colorblindness
X-Linked Inheritance: Dominant/Recessive
Dominant more prevalent in females than males (lethal to males, miscarriage)
Recessive almost exclusive in males, female carriers may have milder symptoms, rare for female to be homozygote
X-Linked Dominant Pedigree
Affected male’s daughters are all affected
Affected male’s sons never affected
Affected female’s children at 50% risk
Males more severely affected, may be lethal
Incontinentia Pigmenti
X-Linked Dominant
Skin redness and blisters, thickened skin progression then hyper-pigmentation
Mostly neurologically normal
Seen only in females (males miscarried)
NEMO gene
X-Linked Recessive Pedigree
More affected males than females
Male grandfather to male grandson transmission through female carrier (daughter)
No male-male transmission
X-Linked Recessive Disorders (examples)
Hemophilia A and B
Duchenne Muscular Dystrophy
Red-Green Color Blindness
Hemophilia A
X-linked recessive
Reduced factor VIII (reduced clot factor)
Excessive bleeding
Amount of factor VIII determines clinical severity (less than 1% is severe, 6%+ is mild)
Can give them factor VIII for treatment
European Royalty Pedigree (inbreeding)
Duchenne Muscular Dystrophy
X-Linked Recessive
Normal at birth, progressive muscle weakness, wheelchair age 10, progression to death, pseudohypertrophy, respiratory insufficiency
DMD gene on Xp21 (dystrophin protein)
Mutations primarily deletions
1/3 cases are new mutations, rest has female carrier mother
Carrier women asymptomatic, may have elevated creatine kinase levels (detect biochemically or genetically)
Duchenne Muscular Dystrophy (Muscle Biopsy)
Variation in fiber size
Proliferation of connective tissue
Degeneration, necrosis, phagocytosis of muscle fibers
Red-Green Colorblindness
X-Linked Recessive
8% of men, 0.5% of women
Cones- red, green, blue
Red/green opsin gene one X
Blue opsin gene on autosomal
Normally females got red and green opsins
Crossing over can be unequal (more on one X chromosome than other or mixing of green and red opsin, bunch of options)
X-Linked Recessive Disorders in Females (How)
Skewed X-inactivation patterns
- random (most common)
- failure of cells with mutant X to survive (some immune disorders)
Only one X chromosome (Turner Syndrome)
Translocations or deletions involving X-chromosome
