Download BIOL 311 Human Genetics

BIOL 311 Human Genetics
Fall 2006
Lecture: Molecular Pathology
Reading: Chapter 16
Lecture outline:
1. Molecular approaches to disease
2. Loss of function mutations
3. Gain of function mutations
4. Examples of mutations causing human diseases
5. Triplet expansion diseases
Lecture:
1. Molecular approaches to disease
Pathology: the study of disease.
Molecular pathology: finding the underlying genetic or biochemical basis for the
disease
Genetic variation that leads to disease not always easy to distinguish from random
genetic change (polymorphism).
2. Loss of function mutations
Mutant DNA defective RNA protein with reduced function or no function
Types of mutations leading to loss of function
 Small insertions or deletions--shift reading frame "frameshift mutants"
 Nonsense mutations
 Nucleotide changes that result in premature stop codons
 mRNAs with premature stop codons are usually degraded
 Splicing mutations
 Alteration of splice junctions or "branch points"
 Alter regulatory elements that regulate splicing (splicing enhancers or silencers)
Usually loss of function mutations are recessive, however some show incomplete
dominance or "haploinsufficiency"--where one good copy is not sufficient to restore
function.
Dominant negative effect--when a mutant polypeptide loses function and interferes with
product of the normal allele.
 Seen in proteins that form dimers and multimers, i.e. collagen, transcription
factors.
3. Gain of function mutation
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
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Gene product does something positively abnormal
Usually requires a specific change; other mutations in the same gene give a
different phenotype.
Single types of mutation leading to disease can be due to
 Specific mechanism of change, i.e. triplet expansion.
 Founder effect--a deleterious mutation in a small population is source of major
type of mutation
 Heterozygote selection
Gain of function common in genes involved in cancer. Gain of function mutations
activating cell signaling pathways often produce dominant phenotypes.
Can have gain of function and loss of function mutations in same gene leading to
different diseases.
4. Examples of molecular bases for diseases
a. Hemoglobinopathies: diseases of hemoglobins
Single nt substitution at amino acid #6 of beta-globin causes sickle cell anemia.
Thalessemias
 Not enough alpha or beta globin chains, leads to anemias
 α0 thalessemia: no alpha globin
 α+ thalessemia: reduced levels of alpha globin
Fig. 16-3 deletions in globin genes due to unequal crossover
Table 16-1 lists 11 ways to reduce or abolish production of functioning gene product.
5. Triplet expansion diseases
 discovered as disease mechanism in 1991
 show anticipation--age of onset is lower and severity is worse in subsequent
generations.
 At least eight diseases show triplet expansion
 Two classes of triplet expansions that cause disease (5'UTR, intron, 3'UTR)
 Large expansions of repeats outside coding sequences
Fragile X syndrome
Mental retardation syndrome
(CGG)n repeat in 5'UTR
stable @ 6-54 copies
unstable @ 200-1000+ copies
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Other diseases:
Friedreich Ataxia
Myotonic dystrophy (2 genes)
Spinocerebellar ataxia (2 genes)
 Modest expansion of CAG repeats within coding sequences encoding
polyglutamine.
 Late onset neurodegenerative disorders, all but one dominantly inherited
Huntington Disease (CAG)n
Stable # repeats 6-35
Unstable # repeats 36-100+
Polyglutamine diseases, Alzheimers, Parkinsons have in common protein aggregation.
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