Genetic Basis Of Human Disease: Monogenic Disorders and Cancer Flashcards
1
Q
Archibald Garrod
A
- founder of biochemical genetics
- originator of concept of “inborn errors of metabolism” (1909)
- Discovered Alkaptonuria
- Lead to identification of other inherited metabolic disorders
- Alibinism (tyrosinase defect)
- Phenylketonuria
- Cystinuria
- Glycogen storage disorders
- Galactosaemia
2
Q
Alkaptonuria
- Mode of inheritance
- Cause
- Pathogenesis
A
- Identified by Archibald Garrod
- Inherited as classical autosomal recessive trait
- Defect in enzyme Homogentisate 1,2 Dioygenase
- So homogentisic acid is not converted to maleylacetoacetic acid
- Acid accumulates in joints
- causes cartilage damage
- back pain
- precipitates as kidney and prostate stones
- high levels are excreted - blackening urine
- allows diagnosis
3
Q
William Bateson
A
- Began cataloguing human diseases that exhibited Mendelian Inheritance
- 1909
4
Q
4 Types Of Mendelian Patterns Of Inheritance
A
- Autosomal recessive
- Alkaptonuria
- Cystic fibrosis
- Autosomal dominant
- Huntington’s disease
- Brachydactyly
- Autosomal co-dominant
- Sickle-cell anaemia
- X-linked: limited to males (mostly)
- Duchenne Muscular dystrophy
- X-linked mental retardation
- Haemophilia
5
Q
Sickle-cell anaemia (SCA)
- inheritance
- molecular basis
A
- ID by Linus Pauling, 1949
- Painful, sometimes life threatening disorder of erythrocytes
- Alleles exibit co-dominance: “sickle-cell trait”
- Haemoglobin is a tetramer of 2a-globin and 2B-globin protein subunits
- SCA is caused by a single point mutation in B-globin subunit
- Subunit becomes ‘sticky’ and aggregate together (form large insoluable polymers) and precipitate out
- can form rods - distort erythrocyte shape
- Effects ability of rbc to bind and take up oxygen sufficiently
6
Q
Sickle-cell anaemia (SCA)
- Prevalence
- Carriers
A
- Prevalence: ~2% in some sub-Saharan countries
- Heterozygous carrier frequency = 10-40%
- Carriers have SC trait but exhibit increased resistance to malaria
- fitter than normal and SCA homozygous
7
Q
Karyotyping
A
- 1970s
- Allows each chromosome to be distinguished
- Enables genes to be mapped to specific chromosomal locations
- Abnormalities in banding due to mutagenic rearrangements can be recognised and associated with specific phenotypes
- Changes at karyotypic level can be linked to changes at phenotypic level by looking at banding patterns
- (Before karyotyping a few genes had been assigned to X-chromosome due to sex-linked patterns of inheritance)
8
Q
Duchenne Muscular Dystrophy (DMD)
A
- X-linked
- Progressive muscle damage and wasting
- lethal in childhood/ early adulthood
- ID by looking at banding patterns on X-chromosome
- a DNA sequence deleted on X-chromosome of DMD pts
- DNA marker DXS164 (part of gene encoding dystrophin protein) mapped to a specific region on X-chromosome
- Dystrophin
- largest known human gene
- part of a bridging complex connecting each mucle fibre to the ECM
- maintaining tissue integrity
9
Q
Huntington’s Disease (HD)
Molecular basis
A
- Autosomal dominant
- progressive, late-onset, neurodegenerative disorder
- First described by George Huntington, 1872
- A dementia and movement disorder
- Brain exhibits massive neuronal loss in basal ganglia
- Karyotypic abnormalities on chromosome 4
- “drilled down” to find affected gene
- HD mutations expand a CAG repeat sequence in first exon of HD gene
- increases size of polyglutamate tract in HD protein (PolyQ)
- Causes HD protein to form aggregates
- Expanded polyQ tract makes HD protein toxic to neurons
10
Q
Rous Sarcoma Virus
A
- 1st tumour-causing virus discovered
- Peyton Rous 1911
- Tumorigenicity due to prescence of DNA sequences captured from chicken genome
- v-src oncogene
- Virus appropriates cellular gene
- V-src encodes an abnormally hyperactive version of a tyrosine kinase encoded by a cellular gene (c-src proto-oncogene)
11
Q
Virus oncogenes (v-onc)
A
- dominant, gain of function mutant alleles of cellular proto-oncogenes
12
Q
Chromosomal Rearrangements
A
Can cause cancer if:
disrupt,
truncate,
or reassemble
cellular proto-oncogenes
13
Q
Chronic Myelogenous Leukaemia
A
- Chromosomal translocation in haemopoietic progenitor cells (blood stem cells)
- creates “Philadelphia Chromosome”
- BCR-ABL encodes an abnormally hyperactive version of tyrosine kinase encoded by cellular ABL1 proto-oncogene, lacking normal ABL1 N-terminal domain
14
Q
Retinoblastoma
A
- Rare retinal tumour (hereditory/non-hereditory)
- Tumours may be unilateral/ bilateral
- Alfred Knudson’s hypothesis:
- retinoblastoma is caused by mutation in tumour suppressor gene that normally prevents cell beoming cancerous.
- 2 hit hypothesis:
- retinoblastoma caused by inactivation of both alleles of a tumour suppressor gene
- insight: individuals born heterzygous for a recessive mutation in retinoblastoma gene will develop tumours in either eye with equal probability if independent secondary mutations inactivate remaining wild-type copy
- Unolateral retinoblastoma can be hereditory/ non-hereditory
- Bilateral retinoblasoma is hereditory
15
Q
Neurofibromasts Type 1
(NF1)
A
- Benign tumour of peripheral nerve sheath myelinating Schwann cells
- Individuals are NF1 heterozygous
- Tumours are homozygous
- Mutated gene encoded Neurofibromin 2, ID by positional cloning
- NF1 encodes an inhibitory regulatory protein that regulates activity of oncogenic GTP-ases eg RAS
- Loss of both copies releases RAS from regulation
- Pts with NF1 inherit 1 inactive allele, present in all cells, but inactivation of second copy in Schwann cell transforms them into tumour cells
