Lecture 2: Genetic Basis of Human Disease Flashcards
Archibald Garrod was the
Founder of Biochemical Genetics Originator of the concept of : Inborn Errors of Metabolism “ 1909
Archibald Garrod looked at the disease
Alkaptonuria
Alkapatonuria is a
defect in the enzyme Homogentisate 1,2 Dioxygenase
Alkaptonuria causes
Homogentisic acid accumulates in joints, causing cartilage damage & back pain; precipitates as kidney / prostate stones; high levels are excreted, blackening urine - allows diagnosis.
what allows diagnosis of alkaptonuria
BLACKENING URINE
Garrods discovery that Alkaptonuria was inherited as a ____ led to
AUTOSOMAL RECESSIVE
..led to the identification of other inherited metabolic diseases
other inherited metabolic diseases after Garrod did
Cystinuria Phenylketonuria Albinism (tyrosinase defect) Glycogen Storage Disorders Galactosaemia
William Bateson began to
catalogue human diseases that exhibited Mendelian Inheritance (1909)
- skin disorders
- eye disorders
- neurological disorders
- inborn errors of metabolism
- anatomical abnormalities
skin disorders:
- Epidermolysis bullosa
- multiple telangiectasia
eye disorders:
Aniridia, red-green colour blindness
Neurological disorders
Huntingtons, chorea
Inborn Errors of metabolism
Alkaptonuria (after Garrod), haemophilia
Anatomical abnormalities
Brachydactyly (short digits)
Autosomal recessive
Alkaptonuria, Cystic Fibrosis
Autosomal dominant
Brachydactyly
Huntington’s Disease
Autosomal co-dominant
sickle cell anaemia
x-linked: limited to males (mostly)
Duchenne Muscular Dystrophy
X-linked mental retardation
Haemophilia
Sickle cell anaemia is
painful, sometimes life-threatening disorder of erythrocytes
haemoglobin is a
tetramer of 2 α-globin and 2 β-globin
protein subunits
sickle cell anaemia is cause by
a single point mutation in the codon for amino acid 6
in the β-globin subunit
Glu codon Val codon
Haemoglobin tetramers
Containing HbS tend to form large insoluble polymers which distort erythrocyte shape
SCA and malaria:
Heterozygous carriers of HbS have Sickle Cell Trait but exhibit increased resistance to malaria – Heterozygotes are fitter than HbA and HbS homozygotes
Hb^A and Hb^s alleles exhibit
co-dominance, i.e. heterozygote sickle cell phenotype is intermediate between wild-type and Sickle Cell Anaemia – “Sickle Cell Trait”
co-dominance
genetic scenario where neither allele is dominant or recessive and both get expressed
karyotyping allows
each chromosome to be distinguished.
Until karyotyping became possible in the ___, the human genome was almost
entirely uncharted territory.
Until karyotyping became possible in the 1970s, the human genome was almost
entirely uncharted territory.
A few genes had been assigned to the X-chromosome because of their Sex-linked
inheritance patterns.
in Karyotyping abnormalities in banding
due to mutagenic
rearrangements can
be recognised and
associated with specific phenotypes.
karyotyping allows
genes to be mapped to specific chromosomal locations.
Aniridia
an autosomal dominant phenotype caused by
deletion or loss-of-function point mutations in one copy of the gene
Duchenne muscular dystrophy (DMD) is an
X LINKED DISEASE
Progressive muscle damage and wasting disease
Lethal in childhood or early adulthood
DMD gene located at chromosome position Xp21
DMD gene was identified by a DNA sequence that was
deleted
whats the largest known human gene
dystrophin (>2 x10^6 bp gene encoding a >3500 a.a. protein )
Dystrophin protein is part of a
bridging complex connecting each muscle fibre to the extra cellular matrix, thus maintaining tissue integrity
Huntington’s disease is a —- and discovered by
progressive, late-onset, inherited
neurodegenerative disorder.
A dementia and movement disorder, first described by George Huntington (1872)
HD gene is approx
1.7 x 10^5 base pairs in size
molecular pathology of HD
HD mutations expand a CAG repeat sequence in the first exon of the HD gene, increasing the size of a polyglutamine tract in the HD protein.
wild 10-35 glutamine residues
HD patients 36-121 glutamine residues
the expanded polyQ tract makes the
mutant Huntingtin protein toxic to neurons.
some animal virus genomes contain
genes that cause cancer
Peyton Rous
1879-1970
was the first to discover a tumour-causing virus:
Rous Sarcoma Virus (1911
Tumorigenicity of Rous Sarcoma Virus is due to
presence of DNA sequences captured from the
chicken genome - the v-src oncogene
v-src encodes an abnormally hyperactive version of a tyrosine kinase encoded by
a cellular gene - the c-src proto-oncogene
examples of viruses that have been discovered to contain oncogenic mutant versions of host cellular porto-oncogenes (v-onc)
Rous Sarcoma Virus (v-src)
Harvey Murine Leukaemia Virus (v-H-ras)
Avian Erythroblastosis Virus (v-erbB)
Mouse Mammary Tumour Virus (wnt-1)
Abelson Murine Leukaemia Virus (v-abl)
viral oncogenes are
Dominant, gain-of-function mutant alleles of cellular genes
Chromosomal rearrangements that disrupt, truncate, or reassemble
cellular proto-oncogenes can cause
cancer
Chronic Myelogenous Leukaemia is caused by
a chromosomal translocation in haemopoietic progenitor cells that creates the “Philadelphia Chromosome”
Loss of function mutation cause
cancer
.……by inactivation of tumour suppressor genes, e.g. Retinoblastoma
retinoblastoma is a
rare retinal tumour that can be either
hereditary or non-hereditary
tumours can be
unilateral or bilateral
Non-hereditary retinoblastomas are typically _____
BUT
Hereditary retinoblastomas are typically ____
unilateral
BUT
bilateral
Alfred Knudsons hypothesis
that retinoblastoma is caused by mutations in a Tumour Suppressor gene that normally prevents cells from becoming cancerous
Alfred Knudsons Two-hit hypothesis states that
retinoblastoma
is caused by inactivation of both alleles of a Tumour Suppressor gene
Alfred Knudson’s insight:
Individuals who are born heterozygous for a recessive mutation in the
Retinoblastoma gene will develop tumours in both eyes if independent secondary
mutations inactivate the remaining wild-type copy in cells of each eye
steps for retinoblastoma Alfred Knudons theory
Non-hereditary retonibloastoma: -first somatic RB mutation acquired in retinal cell -second somatic RB mutation acquired in retinal cell (rare to be in same cell)
Hereditary retinoblastoma: -Inherited germline mutation present in all cells -first somatic RB mutation acquired in retinal cell
Many human diseases are caused by
single gene defects
Advances in molecular biology enables disease genes to
be identified solely on
the basis of their chromosomal position
without prior knowledge of the functions of their proteins
Cancer:
caused by dominant, gain-of-function mutations in
Proto-oncogenes
Cancer: caused by recessive, loss-of-function mutations in
Tumour supressor genes
