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MM17: Mendelian Genetics 3 (ii) (Epigenetic/genomic imprinting (reversible…
MM17: Mendelian Genetics 3 (ii)
alpha 1 antitrypsin deficiency
a1 antitrypsin = Serine protease inhibitor (SERPIN)
inhibits elastase in lung
SERPINA1 gene mutations
misshapen enzyme, gets stuck in liver, can't get to ling, excess elastase destroys pul alveoli
gene = highly polymorphic (>100 alleles)
in Europe, most common mutations are M (normal), S (increased COPD risk), Z (most increase in COPD risk)
1 mutant allele: 50% enzyme activity (increases emphysema risk 20-fold)
ZZ genotype most @ risk
leads to emphysema (severe COPD)
smoking = environmental risk factor
Epigenetic/genomic imprinting
heritable phenotypes that don't involve changes in DNA sequence
reversible chemical modifications of DNA via a discrete event
usually DNA methylation @ promotors (5' end)
usually causes gene silencing
only occurs in specific regions of genome
parent of origin: sometimes a phenotype depends on gene expression differences as a result of genomic imprinting
most genes aren't imprinted
hence most autosomal allele mutations are equally maternally or paternally transmitted
imprinted genes stay stable in mitosis-> persist in somatic tissue
reversible in gametogenesis
silencing lifted via demethylation, both alleles active
biallelic expression
epigenetic reprogramming
then imprinting reestablished
15q has lots of imprinted genes...
Prader-willi syndrome
15q11 deletion from father, silenced from mother - SNRPN gene absent
dysmorphia, obesity, constant eating, small hands/feet, hypogonadism, cognitive impairment
Angelman syndrome
15q11 deletion from mother, silenced from father - UBE3A gene absent
dysmorphia, unusual facial features, short stature, severe cognitive impairment, seizures
other epigenetic changes causing disease
hypomethylation: colon cancer
hypoacetylation: silencing of tumour supressor genes
loss of imprinting: Wilm's tumour
both IGF2 alleles expressed instead of just paternal
cancer = genetic + epigenetic combination