G8 Flashcards
describe an autosomal dominant inheritance and and give an example
half of offspring affected
unaffected individual doesnt transmit disease
eg. Anchroplasia - dwarfism
describe an autosomal recessive inheritance and give an example
ussually only one generation affected
if both parents carriers = 1/4 affect, 1/2 carries, 1/4 not affects
eg. CF
What is X linked recessive inheritance and give an example
carrier females transmit disease to half their sons and carrier status to half their daughters
eg. X linked haemophilia
c.76A>T
substitution A->T in coding DNA
c.76_78delACT
range of affected resieus 76-78 by deletion of ACT
c.76dupA
duplication at 76 of A base
c.76delA
deletion at 76 of A
c.76-83inv
inversion between 76 and 83
c.76_77insG
insertion but it duplication describe as duplication
G inserted between 76 adn 77
p:Lys76Asn
p refers to primary translation product
at AA 76 varient results in sub of asparagine instead of normal lysine
p.Tyr356X
X indicates a nonsense codon has been generated
c.1408+2T>G
second nucleotide after c.1408 that would normally be the invariant T of splice site is insead a G
c.789-1G>A
first nucletodie before c.780 that would normally be invariant G of splice site is now an A
c.69_71del(p.Val15del)
in frsame deletion deletes aa valine
c.546insA(p.Val170fs)
out of frame insertion inserted valine causing frameshift after 170
what letters denote each type of reference seqeunce
c= coding DNA g- genomic DNA r = coding RNA reference seq n = non coding RNA ref seq m = mitochondrial DNA seq
What is HGVS
human genome variation society
what terms do HGVS use to prevent confusion from using terms like SNP or mutation
sequence variatn
alteration
allelic variant
what classes and terms do HGVS use to recognise that some variants can be harmful
5 = affects function 4 = probs affects function 3 = unknown 2- probs doesnt affect function 1= doesnt affect function
what casues anchrondoplasia
Fibroblast growth factor receptor 3 p FGFR3 - represses ossification of chondrocytes that proliferate and mature into bones at growth plate
- in anchondroplasia ossification is further pressed
what is ossification
process where catilage is turned into bone
why is it difficult to predict what the ouctome of splice site mutations will be?
as genes use alternate transcriptional start sites, alternate combos of exons, althhough usually one isoform RNA is shown, cell can produce several different ones at the same time and this remains poorly understood
what is nonsense mediated decay?
highly conserved quality control survelliance mechanism
recongises and degrades defective mRNAs with premature termination codons PTCs which if translated could produce harmful aberrant proteins
(can occur indep of any DNA mutations as a result of errors during transcription, processing or packaging)
what happens to EJCs in normal splicing and i PTC containing mRNA
normal: proteins of exon junction complec = deposited 2-24 nts upstream of each exon/exon unction, and are displaced by scanning ribosome during inital round of translation.
PTC: upon recognition of stop codon, a termination complex is fomred, in PTC containing mRNA, EJCS downstream of PCR are not displaced allowing the termination complex to interact with the EJC triggering NMD.
why do premature stop codons lead to
not neccessarily truncated proteins = often no protein at all through NMD
What could PTC read through do?
override NMD degradation mechanisms and allow some proteins to be produced from mutant mRNAs - pioneered in the field of DMD
= clinical practice
what do most cases of CF result from
phe580del
change in F508, 3nt deletion, deleting phenylalanine at position 508. created a misfolded protein which is usually degraded in ER, poorly function if does reach cell surface.
what kind of mutation is DMD usually caused by
frameshift and nonsense mutations
what kind of mutation is backer muscular dystrophy caused by
inframe deletion or change in expression
how is it theoretically possible to convert faulty mRNA to produce product
inducing exon skips using antisense constructs and produce an inframe mutation without the framshift nonsense codon
what can inframe deletions be
- disease causing as in CFTR - Phe508
- better than no protein at all as in dystrophin
- tolerated with no apaprent ill effect (as heterozygote)
Describe the case study of the mutation on ENG
endoglin gene (ENG) causing HHT - autosomal dominant disease causing nosebleeds and abnormal blood vessels, only 2/3 children had HHT = not possible, so found that it was just an endoglin missense polymorphism that had been overinterpreted, seqeunce change was not in pahse with true diesease causing gene.
