Single Cell Disorder Flashcards
PKU
insufficient phenylalanine hydroxylase activity (phenylalanine > tyrosine)
so can’t degrade phenylalanine = intell dis
treat with phenylalanine free diet
autosomal recessive
recessive disorders
only homozygous indivs w/ two mutant alleles affected
heterozygous indivs w/ one mutant allele is carrier
-if both parents carriers = 25% kids affected + 50% carrier kids + 25% unaffected
recessive inheritance
if loss of one allele can be compensated aka defects in highly regulated processes OR
enzyme defect
inborn errors of metabolism= family of recessive disorders
consanguinity
same blood/related
inc risk for recessive dis esp if rare aka homozygous by descent
children of 1st cousin unions F= 1/16
F = coefficient of consanguinity
dominant inheritance
cause disease in heterozygous state so one mutant allele is bad (second normal copy not compensate)
affected children have at least one affected parent
haploinsufficiency
one intact allele not enough to maintain function
-receptor mutations aka LDL = familial hypercholsterolemia
-when amount of protein matters more than activity
-protein activity not regulated
-paracine/endocrine messangers (sonic hedgehog)
dominant negative effect
mutation = protein that interferes w/ normal function , often when protein part of larger structure i.e collagen
- null (completely destroys)
- missense (change sequence)
gain of function
mutation = protein w/ new function
-signaling proteins so activate cascade w/o ligand binding
dwarfism/achondroplasia from growth factor receptor misfiring (FGFR3)
Two Hit Model
Loss of Heterozygosity
- mutation in tumor suppressor to predispose to cancer
- somatic mutations disable the second intact copy = lose heterozygosity
cancer i.e retinoblastoma (bilateral, onset before age 5)
x-linked recessive inheritance
-skips generations through carrier females
-males > X to all daughters so will be carriers if affected father
-males > Y to all sons so no father-son transmission
mosaicism
in females:
one X is inactivated during dev randomlly and fixed SO
mosaic for x-linked traits
Duchenne Muscular Dystrophy
mosaicism = carrier females have mix of cells with and w/o hystrophin, will not be fully normal but not meet diagnostic criteria
affected males have no dystrophin in muscles
mitochondrial disorders
all mitochondria passed from mother
-not follow mendelian rules so varying fractions in egg + unpredictable severity +
heteroplasmy = uneven distribution of mito w/ mutations during mitosis
codominant inheritance
both alleles of a gene produce distinguishable trait and are both expressed
i.e MN glycoprotein on RBCs
diagnostic criteria
familial hypercholesterolemia
diagnosed with FH if
1. heterozygous, dominant dis when threshold low, x2 the LDL
2. or homozygous, recessive dis when threshold high, x4 LDL
heterogeneity
one disorder caused by diff mutations
can be:
locus: in diff chromosomal loci/genes
allelic: diff mutation in same locus/gene
pleiotropy
one mutation cause more than one disorder or affect multi systems so overlap possible
risk of seeing diff providers for the same disease
locus heterogeneity
mutations in diff loci/genes cause same disease
-proteins that require processing/trafficking (ECM proteins, collagen) OR
defect in processing
allelic heterogeneity
diff mutations on same locus/gene cause same disease
-null mutation = haploinsufficiency
-missense mutation = dominant negative effect
peripheral mutation not as bad as a central
Osteogenesis Imperfecta
disorder of type I collagen (mutation in COL1A1 or COL1A2) = deficienccy in bone formation
-type I = blue sclerae, balance issues, bruising, from COL1A1 = haploinsufficient
-type II = perinatally lethal, severe, COL1A2 = dominant negative effect
-type VIII = loss of function mutations in P3H1 gene so recessive inheritance
Collagen Assembly Mutations
mutation in collagen processing enzymes = recessive forms of OI
vs
mutation in collagen genes = dominant OI
dominant negative mut can be more severe than null muts
Neurofibromatosis type 1
NF1
autosomal dominant disorder (parent > kid)
complete penetrance and variable expressivity
penetrance
% of people w/ mutation who dev symptoms
disorders can skip generations when low penetrance so still passed on just not symptomatic
all or nothing
expressivity
how patient presents/phenotypes
can lead to missed diagnoses if mild or diff in parents and children
achondroplasia
dwarfism
gain of function mut in FGFR3
fully penetrant + narrow variation in expressivity aka all present similar
short limbs, enlarged neurocranium, midface hypoplasia
new mutations and fitness
new will occur in diseases that affected indivs have low fitness aka low chance of reproducing OR
-large genes (broad target)
-genes with mutation hotspots
if fitness is 0 (all affected indivs die/not reproduce) then any case must be from new mutation
correlated with advanced paternal age
Huntington disease
100% penetrance + narrow variation of expressivity aka diagnosis cannot be missed
from triplet repeat
inc involuntary muscle movements, inc moody/depressive behavior
inc severity = earlier age of onset
triplet repeats
pre-mutation: 35-40 repeat expansions , risk of having multiple affected children bc expansion during gametogenesis
full mutation : dominant mode of inheritance
anticipation: children more severly affected than parents
anticipation
repeat length inc = severity inc
repeats @UTR, exons, introns
