Week 2 Flashcards
—————- : a type of gene mutation in which the addition or deletion of one or more nucleotides causes a shift in the reading frame of the codons in the mRNA, which may lead to the alteration in the amino acid sequence at protein translation.
frameshift
Synonymous vs Non-Synonymous Substitution
- Synonymous –> silent (no effect on the amino acid )
- Non-synonymous –> Missense / nonsense (alters an amino acid which may produce a malfunctioning protein)
Nonsense vs missense mutation
Missense: substituation of a different amino acid into the amino acid sequence as a result of the nucleotide change
Nonsense: a point mutation which introduces a premature stop codon into mRNA sequence as a result of a nucleotide change.
what type of mutation causes Cystic Fibrosis?
Loss of fxn on the CFTR gene
what type of mutation is Duchenne muscular dytrophy (DMD) + Mode of inheritance
Type: out-frame mutation on the Dystrophin gene
mode : X-linked recessive (XLR)
Clinical presentations of Duchenne Muscular dystrophy (DMD)
1) Progressive muscle weakness
2) Wheelchair dependency
3) delayed motor milestones
4) cardiomyopathy
Clnical case
- 3-year-old boy
- Unable to run
- Muscle weakness
- Uncle died at age 21 and was on wheelchair
- Muscle biopsy
- Loss-of-function mutations in the Dystrophin gene (X-linked recessive)
- Mostly deletions of part or all of the gene
Disorder?
DMD - Duchenne muscular Dystrophy
Give an example of a disease caused by an inframe mutation (Gain of function mutation )
Beckers muscular Dystrophy
*some Dystrophin produced
clinical case:
* 6-year-old girl
* Multiple fractures/ minor trauma
* Blue sclera
* Abnormal structural integrity of bones
disease?
Osteogenesis Imperfecta (OI type IV)
Osteogenesis Imperfecta are caused by Altered structures of ? what type of mutation?
type: Dominant negative mutations
altered sturctures: pro α1(1)/ pro α2(1) chains/ Integration into triple helix
Type of mutation of Type I OI
Nonsense mutation
Type of mutation of Type II-IV OI
Missense, dominant negative
what syndrome is missing chromosome 4?
Wolf-Hirschhorn syndrome, Huntington chorea, Achondroplasia
Why do people with Wolf-Hirschorn (WHS) do not develope Huntington Disease or Achondroplasia ?
Becasue they 4p gene is delelted at different regions
Wolf-Hirschhorn syndrome (4p-)
HD (4p16.3)
Ach- FGFR3 (4p16.3)
Type of mutation of Osteogenesis Imperfecta (COL1A1 vs COL1A2)
COL1A1–> dominant negative
COL1A2 –> loss of function
Clinical case:
* 4-year-old boy
* Unusual skin pigmentation- 7 Café-au-lait macules > 5mm
* spine –> mild scoliosis
* Optic glioma
* Multiple Lisch nodules (iris hamartomas)
Disroder?
NF1 - Neurofibromatosis Type 1
Lisch nodules
————- The fraction/proportion of individuals with a genotype known to cause a disease who have any signs or symptoms of the disease
- Does not involve severity of the disease
- Can be aged-dependent
Penetrance
MoI + type of mutation of Hereditary Breast and Ovarian cancer?
*MoI : mode of inheritance
MoI : Autosomal dominant inheritance (AD)
mutations in : BRCA1/2
* Reduced penetrance (Females have 87% risk , males have 20% risk)
Reduced penetrance typically described for autosomal [dominant/recessive] diseases
Dominant
Note:
can also apply to recessive ones (e.g.haemochromatosis)
Autosomal recessive disease w/ Reduced penetrance
Haemochromatosis
MoI of Huntington disease
Autosomal dominant
cause of Huntington disease
CAG trinucleotide repeat expansion in HTT gene
(ON an EXON)
CF of Huntington disease
Motor:
involunary –> chorea, rigidity, dystonia
Voluntary –> Clumsines, dysarthria, visual gaze
Cognitive: global decline in cognitive abilities
Psychiatric: depression, personality changes (bioplar), psychosis
Mean age of onset: late 30’s-40’s (Anticipation is observed)
Triade of clinical findings: motor, cognitive, Psychiatric
Normal CAG count?
6-26 repeats
* no risk of developing HD and no known risk to children
Intermediate alleles of Huntingtin genes
27-35 CAG repeates
- No risk for HD, but a small risk to children (more likely if paternal transmission)
Reduced penetrance allele of HD
36-39 CAG repeats
* May develop HD and 50% risk to children
Complete penetrance allele for HD
>40 CAG repeates
* will develop HD and a 50% risk to children
MoI of Tuberous sclerosis
AD , full penetrance
Allelic vs locus heterogeneity
Allelic : genetic disorder caused by many mutations in the same gene
Locus: mutations in a number of different genes
A disease w/ marked Allelic heterogeneity
Cystic fibrosis (CFTR mutations)
Diseases that exhibit Locus Heterogeneity
1) Tuberous sclerosis (TSC1 & TSC2)
2) Hereditary Multiple Osteochondromas (EXT1 & EXT2)
3) Non-syndromic retinitis pimentosa
————– is the variation in the severity of a disorder in individuals who have inherited mutations in the same gene or even the same disease alleles (extent to which a genetic defect is expressed)
Variable expressivity
——————- : chromosomes of a pair are inherited from same parent, instead of one being inherited from the father and the other from the mother.’
Uniparental Disomy (UPD)
Isodisomy vs heterodisomy
Heterodisomy means that both parental homologues are present, while isodisomy refers to the presence of two copies of one parental homologue
CF of Angelman Syndrome (‘Happy puppet’ Syndrome)
- Ataxia (loss of coordination)
- Developmental delay
- Microcephaly
- seizures
- Minimal use of words
- Behavioural: excitability , frequent laughter
- Wide mouth (spaced out teeth)
- Prognathism ( protruding large lower jaw)
- light coloured skin, hair, and eyes
- Characterisitic EEG
Angelman Syndrome is cause by what type of mutation?
loss of function of maternally inherited UBE3A gene at 15q11-q13
CF of Parder-Willi Syndrome (PWS)
- Infancy -> hypotonia (flapping), Feeding difficulties
- Later –> excessive eating, obesity
- Developmental delay
- Hypogonadism (reduced testosterone production)
- Short stature
- Bitemporal narrowing
- Palpebral fissures (almond-shaped, slightly upslanting)
Parder-Willi Syndrome are caused by what type of mutation?
Microdeletetion of Paternally inherited genes at 15q11-q13 SNPRN,NECDIN
CF of Beckwith-Wiedmann Syndrome
- Overgrowth syndrome, macrosomia (big baby)
- Macroglossia(large tougue)
- Hypoglycaemia (neonatal)
- Umbilical hernia
- Asymmetry/ hemihyperplasia
- Embryonal tumours (Wilms, hepatoblastoma)
- Renal anomalies
- Ear creases/ ear pits
Beckwith-Wiedemann Syndrome is casued by what type of Mutation?
MoI: paternal uniparetnal disomy (UPD)
* Mutations in 11p15.5
(or epigenetic changes at DMR1)
Example of a Skewed X-inactivation syndrome
Duchenne muscular dystrophy
MoI: X-linked recessive
Skewed X-inactivation is more common in [males/females]?
females
note: X-linked recessive disorderes such as Duchenne muscular dystrophy
———————– : a process by which one of the copies of the X chromosome is inactivated in therian female mammals
X-chromosome inactivation
————-: Monoallelic expression of certain genes in zygote based on parent of origin
( process by which only one copy of a gene in an individual (either from their mother or their father) is expressed, while the other copy is suppressed)
Genomic imprinting
