Lecture 8 Molecular Medicine

Gene Mutations and Molecular Medicine

What Are Mutations?
- Alteration of one allelic form
of a gene to another.

Genetic mutations: changes in

DNA that are heritable.

Transmittal: (tissue affected)

- somatic vs. germinal

Lecture 8 Molecular Medicine

MUTATIONS
Chromosomal (larger DNA sequences)

Point (a single nucleotide)

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Mutational Effect

Activity reduced
or eliminated

Novel or increased
Activity 3

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POINT mutations

Silent: no change in amino acid

Missense: changes a single amino acid

Lecture 8 Molecular Medicine

POINT mutations
Nonsense: induces stop codon

Fram-eshift: addition or deletion changes

amino acid sequence

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CHROMOSOMAL mutations

Cancer cell

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How are DNA molecules
and mutations analyzed?

Restriction enzymes:
molecular scissors

Gel electrophoresis:
separate nucleic acids by
size

Lecture 8 Molecular Medicine

What DNA changes lead to genetic diseases?
comparative genomics genome prospecting
Single nucleotide
Polymorphism (SNP):
DNA variation
> 1% of population
90% of variation
2/3 C-T

a. survey related
individuals for
SNPs/RFLPs

Restriction fragment length

Polymorphism (RFLP):
alters restriction site
use for allelic genotyping
linkage to disease

b. correlate with
specific
diseases
c. identify molecular
basis for
disease!

Lecture 8 Molecular Medicine

Laboratories
Diseases for which testing
is available

Lecture 8 Molecular Medicine

How do defective
genes/proteins lead to
diseases?

b. Sequence expansions tri-nucleotide repeats

Wild type (WT)

premutated

diseased
1. Fragile X = CGG expansion, mental retardation
6-54 = wt
55-200 = premutation
200-2000 = disease
FMR-1 5UTR
binds mRNAs in neurons

3. myotonic dystrophy = CTG exp.

5 = wt
50 = mild disease
1000 = severe disease
3 UTR (noncoding effect)

2. X-linked muscular atrophy = CAG expansion (Huntingtons)

21 = wt
40-52 = disease
disrupt androgen receptor ORF

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Lecture 8 Molecular Medicine

How do defective genes/proteins lead to diseases?
b. Sequence expansions tri-nucleotide repeats
wt

premutated

diseased
Case Study:
genetests.org

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Three children - 50% risk to inherit Huntington disease from
their father.

Lecture 8 Molecular Medicine

How do defective genes/proteins lead to diseases?
b. Sequence expansions trinucleotide repeats
Case Study: genetests.org
1.

Do they have different risks for developing disease?

>40 = disease

36-39 = reduced penetrance

27-35 = not at risk

Phenotypes dependent on specific mutation
Presymptomatic testing
Resources

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Lecture 8 Molecular Medicine

How do defective genes/proteins lead to diseases?
c. Deletions: large, small - in frame vs. out of frame

Gene structure
2.6mb, 79 exons,
14kb mRNA
~1/3000 Why?
DMD = amorphic (out
of frame)
- onset 2-6yrs old
- rare beyond 30yrs

BMD = hypomorphic (in

frame)
- adolescence/adulthood
- mid late adulthood
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Lecture 8 Molecular Medicine

How Is Genetic Screening Used to Detect Diseases? (>2000)
a. prenatal, newborn, adults (asymptomatic)
b. testing - DNA, protein, metabolites

carrier
mt
wt

How are Genetic Diseases Treated?

a. restricting substrate PKU, limit phenylalanine
b. metabolic inhibitors statins block cholesterol
c. gene therapy restore gene function
d. directed therapeutics (biologics/small molecules)

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Lecture 8 Molecular Medicine

How are Genetic Diseases Treated?
c. gene therapy restore gene
function (>900 trials)

adenovirus
Gene therapy vectors
retrovirus

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Lecture 8 Molecular Medicine

How are Genetic Diseases Treated?
c. gene therapy restore gene function (>900 trials)

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Lecture 8 Molecular Medicine

How are Genetic Diseases Treated?
c. gene therapy restore gene function (>900 trials)

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Lecture 8 Molecular Medicine

Gene classes

Diseases

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