9: Sex-Linked Disorders

Question 1

Lyonization

Answer 1

X Chromosome Inactivation

Question 2

Sex-Linked Inheritance

Answer 2

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

Question 3

Sex-limited traits (don’t confuse with)

Answer 3

Traits limited to expression in one sex though genes in both sexes
(Milk production and cryptorchidism)

Question 4

Sex-influenced (don’t confused with)

Answer 4

Expression of traits influenced by sex hormones

Male pattern baldness

Question 5

Pseudoautosomal Region

Answer 5

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

Question 6

X Chromosome Inactivation

Answer 6

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.

Question 7

X-Chromosome Inactivation (molecular)

Answer 7

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

Question 8

Tortiseshell Cat

Answer 8

Example of X-Chromosome Inactivation

Different colors on fur

Question 9

Hypohidrotic Ectodermal Dysplasia (X-Chromosome Inactivation)

Answer 9

Females can be missing a few teeth or have patches of anhidrosis (mosaic)

Males may have no teeth, anhidrosis and sparse hair

Question 10

Y Chromosome

Answer 10

Testicular Development by SRY
Spermatogenesis-Yq genes

Used to trace male migration, forensics, paternity testing

Question 11

Sex-Linked Genetic Disorders (basic)

Answer 11

All are X-linked, usually recessive

Mutated Y genes produce infertility and not passed on

Question 12

Sex-Linked Genetic Disorders (recurrence risk)

Answer 12

Affected male, 100% daughters will be carriers, 100% sons unaffected

Carrier female, 50% sons affected, 50% daughters will be carriers

Question 13

Sex-Linked Inheritance Examples

Answer 13

Hypohidrotic ectodermal dysplasia

Incontinentia pigmenti

Duchenne muscular dystrophy

Hemophilia A and B

Red/Green colorblindness

Question 14

X-Linked Inheritance: Dominant/Recessive

Answer 14

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

Question 15

X-Linked Dominant Pedigree

Answer 15

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

Question 16

Incontinentia Pigmenti

Answer 16

X-Linked Dominant

Skin redness and blisters, thickened skin progression then hyper-pigmentation

Mostly neurologically normal

Seen only in females (males miscarried)
NEMO gene

Question 17

X-Linked Recessive Pedigree

Answer 17

More affected males than females

Male grandfather to male grandson transmission through female carrier (daughter)

No male-male transmission

Question 18

X-Linked Recessive Disorders (examples)

Answer 18

Hemophilia A and B

Duchenne Muscular Dystrophy

Red-Green Color Blindness

Question 19

Hemophilia A

Answer 19

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)

Question 20

Duchenne Muscular Dystrophy

Answer 20

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)

Question 21

Duchenne Muscular Dystrophy (Muscle Biopsy)

Answer 21

Variation in fiber size
Proliferation of connective tissue
Degeneration, necrosis, phagocytosis of muscle fibers

Question 22

Red-Green Colorblindness

Answer 22

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)

Question 23

X-Linked Recessive Disorders in Females (How)

Answer 23

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