Mutations and single gene defects

Question 1

mutation definition

Answer 1

a heritable alteration or change in the genetic material, usually pathogenic

Question 2

polymorphism definition

Answer 2

a non-pathogenic alteration in DNA which may alter protein function but is not usually deleterious

Question 3

2 main categories of mutations

Answer 3

point mutations and indwells (insertions and deletions)

Question 4

2 main types of point mutation

Answer 4

transition- purine to purine or pyrimidine to pyrimidine

transversion- purine to pyrimidine or vise versa

Question 5

3 different results of a point mutation

Answer 5

synonymous- does not change the amino acid sequence due to the redundancy of the genetic code

missense- replacement of one amino acid by another

nonsense- codon specifying an amino acid replaced by a stop codon, premature termination code

Question 6

notation to show that arginine replaced histone at residue 117

Answer 6

R117H

Question 7

stop codon notation

Answer 7

X

Question 8

What do indels result in?

Answer 8

frameshift mutations and premature termination codons if indeed is not an exact multiple of 3

Question 9

two main non-coding regions to worry about

Answer 9

splice sites for intron removal and mRNA regulatory regions of genes

Question 10

explain effects of mutation in splice site

Answer 10

can result in intron retention, mRNA remains in the nucleus and is not translated, exon skipping

if from is maintained and the number of nucleotides in a skipped exon are a multiple of 3, a truncated protein is formed

if frame is not maintained then frameshift occurs and a premature stop codon is formed and the RNA degraded

Question 11

explain effects of mutation in mRNA regulatory region

Answer 11

insertion can adversely affect transcription which can be blocked

Question 12

3 main effects of mutations

Answer 12

loss of function, gain of function or haploinsufficiency

Question 13

explain loss of function mutations + examples

Answer 13

mutation affects the level of normal mRNA or produces a gene product with reduced or no function

frameshift, nonsense, mutations in regulatory elements such as promotors or enhancers, mutations in critical domain

Question 14

dominant negative effect definition

Answer 14

recessive mutant polypeptide has lost its own function and interferes with the polypeptide of the normal allele

Question 15

gain of function definition

Answer 15

mutation results in a new protein that has gained a function and interferes with others or becomes over expressed

Question 16

haploinsufficiency definition

Answer 16

dominant loss of function, with one copy of the mutant gene which results in 50% of normal signalling, however the cell is unable to tolerate this

Question 17

example of a haploinsufficient condition

Answer 17

Waardenburg syndrome type 1, hearing loss, pigment abnormalities

Question 18

example of gain of function mutation explained

Answer 18

achondroplasia- short limbs, yet normal sized head, body and intelligence

Gly380Arg mutation in FGFR3 gene which results in the receptor signalling in the absence of ligand which inhibits bone growth by inhibiting chondrocyte proliferation and differentiation and therefore preventing endochondral bone growth

Question 19

Triplet repeat definition

Answer 19

a trinucleotide repeat sequence that can become unstable during replication, leading to expansion

Question 20

anticipation definition

Answer 20

a genetic phenomenon where expansion is progressive down the generations, leading to more easy onset disease in offspring than their parents

Question 21

cause of triplet repeat expansion

Answer 21

strand slippage during replication

Question 22

2 examples of triplet repeat disease + TRIPLET

Answer 22

Huntington’s - CAG in exon 1 of chromosome 4q16, Huntingtin gene

Myotonic dystrophy 1 CTG repeat in the 3- untranslated region of the dystrophia myotonic protein kinase gene on chromosome 3q

Question 23

number of repeats and age of onset Huntington’s

Answer 23

more than 35 repeats is likely pathological

more than 60 repeats leads to onset before the age of 25

Question 24

Huntington’s pathology

Answer 24

degeneration of neurones in the basal ganglia and cortical regions of the brain, resulting in an unsteady gait, jerky involuntary movements and later progressive dementia

Question 25

myotonic dystrophy 1 pathology

Answer 25

myotonia means the hyper excitability of muscles, which leads to shaking hands, person cannot let go and cardiac arrhythmias

Question 26

chorea definition

Answer 26

ringing hands

Question 27

conditions where there is a failure or imprinting + gene

Answer 27

prayer-willi syndrome, failure of paternally inherited SNPRN gene

Angelman syndrome, failure of maternally inherited UBE3A

Question 28

three ways of getting Prader Willi

Answer 28

inherit two chromosome 15s from mother

mutation in father’s SNRPN gene

methylation abnormality, upstream of CpG sequence which switches the gene off