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MM17: Mendelian Genetics 3 (i) (Retinitis Pigmentosa (4 locus…
MM17: Mendelian Genetics 3 (i)
Intro
diagnosing inherited disease
history
lab investigations
pedigree analysis
pattern recognition NB...
AD = vertical
AR = horizontal
x-linked = male->male transmission absent
mtDNA = maternal lineage
potential splice site mutations (could destroy exon-intron splicing signal)
frameshift mutations
deletion: 1+ bases removed
insertion: 1+ bases added
SNPs
no DNA gained/lost
synonymous/silent
nonsynonymous/missense (different AA)
nonsense (early stop codon -> truncated protein)
mutations in coding regions = functionally significant
other regions important too (catalytic/regulatory domain, dimerisation/multimerisation domain, promotor, enhancer sequences)
may cause loss/gain of function mutations
locus heterogeneity in complex diseases (metabolic pathway dysfunctions) or complex structural abnormalities (e.g. in eyes + ears)
Mutation Nomenclature
original AA (1 letter for each AA, then codon no., then change (new AA/X-stop codon-del-deletion)
R408W
most common mutation in Ire
@ codon 408 arginine becomes tryptophan
phenylalanine hydroxylase null mutation (<1% enzyme activity)
missense
G542X
F508del
most common cf mutation in Ire
phenylalanine deletion
complete destruction of CFTR
PKU
allelic heterogeneity (>500 known mutations)
different mutations result in different enzyme activity levels
can be predicted using PRA (predicted residual activity)
classical: severe mutation, no activity, <500mg/day tolerable
variant: >500mg/day tolerable
non-PKU hyperphenylalaninaemia: mild, treatment not always needed
mutations of phenylalaline hydroxylase on chromo 12
phenylalanine can't be converted to tyrosine - toxic accumulation
compound heterozygotes: 2 different mutation alleles on gene of both chromos 12
treatment + enzyme cofactor supplements: BH4 (tetrahydrobiopterin)
Ivacaftor
CF drug, increases function of CFTR
increases opening
increases Cl- conductance
ineffective for F508del
Retinitis Pigmentosa
4 locus heterogeneity (>50 identified genes)
group of eye conditions
50-60% AR, 30-40% AD, 5-15% X-linked
abnormalities in photoRs + retinal pigment epithelium
night blindness, tunnel vision, progressive visual loss, total blindness
varied disease progression (from childhood-50y/o)
most diseases are multifactorial
non-Mendelian
includes environment + genetics
e.g CV disease
genetic predispositions
non-mendelian
variation @ several loci, small polygenic accumulative effects
oligogenic
polygenic, but only a few loci