10LP. Role of sex in inheritance Flashcards
Sex-linked inheritance: XR diseases/syndromes
1) Hemophilia A and B
2) Duchenne muscular dystrophy
3) Becker muscular dystrophy
4) Peroxisomal disease (?)
5) OTC deficiency
6) AIS
7) Kallmann syndrome
8) Favism
9) Red-green colour blindness
10) Isolated hypodontia
Hemophilia A and B
- XR inheritance
- Symptoms: Hemarthrosis
Hemophilia A:
- Intrachromosomal rearrangement
Duchenne and Becker muscular dystrophy
XR inheritance
Dystrophin distorted
Duchenne muscular dystrophy: frame-shift mutation
- DMD: mutant X
- Carrier: mosaic X’s
Becker muscular dystrophy: in-frame mutation
Sex-linked inheritance: XD diseases and syndromes
1) Hypophosphatemia
2) Incontinentia pigmenti
3) Fragile X
4) Amelogenesis imperfecta (amelogenin)
Hypophosphatemia
- XD inheritance
- PHEX: phosphate-regulating endopeptidase
- Vitamin D resistant ricketts
Incontinentia pigmenti
XD inheritance
- Also called “melanoblastosis cutis”
- IKBKG mutation
- Gene: NEMO (NF-κB essential modulator)
- Affects the skin, hair, teeth, nails, and central nervous system. Alopecia, hypodontia, abnormal tooth shape, and dystrophic nails are observed
- Lethal in most males (not all)
Fragile X
- XD inheritance - variable penetrance
- CGG repeats
- FMR = affected protein, FMR-1 = affected gene
- Epigenetic modifications: DNA methylation
- Molecular background: when triplet repeat number is >200, CpG islands are hypermethylated -> inhibit transcription of FMR1 gene
- Symptoms: elongated face, large ears, hyperextensible joints, intelectual disability ++
Sex influenced inheritance
Genes on autosomes that has higher penetrance in one sex than the other (e.g baldness in males)
- Dihydrotestosterone (from testosterone by 5α-reductase) affect hair loss postnatally in males
- Androgenetic alopecia (AGA) - several genetic associations found in many chromosomes, but can have to do with androgen receptor on X chr
Sex limited inheritance
Autosomal genes whose expression is limited to one sex only - require specific hormones for expression
- The genes for secondary sex characteristics are sex-limited
Ex: Precocious puberty: P allele expressed only in MALES, but both males and females can transmit the trait
- LHCGR mutation -> testosterone w/o LH stimuli
- AD, but sex limited
Mitochondrial inheritance (homoplasmy, heteroplasmy
Mitochondrial inheritance: maternal
- Homoplasmy: a eukaryotic cell whose copies of mitochondrial DNA are all identical
- Heteroplasmy: the presence of more than one type of organellar genome within a cell or individual
- Bottleneck inheritance gives variation in disease outcome in case of heteroplasmy
Peroxisomal disease
X-linked neonatal Adrenoleukodystrophy (ALD)
- Lack of β oxidation -> accumulation of VLCFAs
- Lethal within 16 months
- Defective ALDP (ABC transporter)
Ornithine transcarbamylase (OTC) deficiency
- OTC convert ornithine + carbamylphosphate-> citrulline in urea cycle
- Deficiency -> increased orotic acid in urine amd hyperammonemia (!)
Androgen insensitivity syndrome (AIS)
XR disorder
- Testosterone receptor mutation
- 46, XY karyotype, but looks like females
Kallmann syndrome
There are XR, AD and AR forms of Kallmann syndrome!!
- Absent olfactory bulbs
- Failure of GnRH-secreting cells to migrate
- KAL1
- Failure to start or finish puberty, often infertile
Favism
G6PD deficiency (XR, ecogenetic disease)
- G6PD: G6P -> 6-phosphogluconate + NADPH
- Heterozygote advantage regarding malaria
- Triggers: broad-bean, anti-malariacs, moth ball, aspirin, sulfonamides, henna
- Symptoms: hemolysis -> jaundice
