Download Biology 212 General Genetics

Biology 212 General Genetics
Lecture 22: Human Genetic Diseases
Spring 2007
Reading: Links are available through the course web page for
“Your genes/Your health” by Cold Spring Harbor Laboratory http://www.ygyh.org/
Lecture outline:
Human diseases due to single gene defects
a. Phenylketonuria
b. Sickle Cell Anemia
c. Huntingtons Disease
d. Duchenne Muscular Dystrophy
e. Cystic Fibrosis
Lecture:
Human diseases for Mendelian traits
 Genes have been isolated that are responsible for a number of genetic diseases
that are due to defects in a single gene that is inherited as predicted by Mendel’s
laws
 To learn more about some of the more common or better studied traits, we will
use a web site
 The Your genes/Your Health site allows you to track the answers to particular
questions regarding the cause, heredity, diagnosis, and treatment of genetic
diseases. Video clips are included from patients, families and health care
workers.
Summary of basic facts on these diseases:
a. Phenylketonuria
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Autosomal recessive trait
Occurs at frequency of 1/12,000 newborns.
Due to defect in gene for a metabolic enzyme, phenylalanine hydroxylase (PAH).
Phenylalanine hydroxylase catalyzes the conversion of phenylalanine to tyrosine
Leads to the accumulation of phenylalanine. In the brain, this can lead to mental
retardation.
Screening of newborns by pricking the heel and collecting the blood on a card. A
sample of the blood is eluted and tested for it’s ability to promote growth of
bacteria due to accumulation of phenylalanine.
Disease can be controlled and mental retardation can be prevented by placing
individuals on a diet low in phenylalanine. Warning labels are placed on some
foods, including those with the artificial sweetener Aspartame (Nutra-Sweet).
Gene for PAH is located on long arm of chromosome 12.
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One common mutation is designated R408W [amino acid 408 is changed from
arginine (R) to tryptophan (W)]
b. Sickle Cell Anemia
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Autosomal recessive trait
More common in individuals of African, East Indian, or Mediterranean origin
In U.S. African Americans, occurs at a frequency of 1:500 births and 1/12
individuals are carriers.
Caused by a single amino acid substitution at amino acid 6 (valine for glutamate)
due to a single nucleotide change in the beta globin gene (GAG codon changed to
GUG).
Diagnosed based on sickle shaped red-blood cells caused by aggregation of
hemoglobin, and symptoms of anemia. Protein electrophoresis can be used to
distinguish the normal (A) and sickle (S) versions of the beta globin protein. DNA
tests involving gain or loss of a restriction site can also be used to distinguish the
alleles.
Defective allele maintained in human populations due to malaria which needs to
natural selection favoring heterozygotes.
The adult beta-globin gene is part of a cluster on chromosome 11. The globin
genes comprise a multi-gene family that evolved by gene duplication.
c. Huntington’s Disease
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Autosomal dominant disease
Affects about 1/10,000 individuals in Europe and the U.S.
Adult onset neurodegenerative disorder. Affected individuals have jerky muscle
movements, personality changes and dementia.
Gene responsible is named huntingtin and maps to the short arm of chromosome 4
(4p16.3).
Affected individuals have an expansion of the sequence CAG of >35 copies. The
greater the number of repeats, the earlier the onset (this phenomenon is called
anticipation).
Individuals with about 40-60 copies develop disease after age 40.
Multiple copies of the CAG sequence within the gene cause the huntingtin protein
to have a long segment of glutamates in the amino acid sequence. This leads to
aggregation of the protein with other proteins, premature cleavage and migration
of the huntingtin protein to the nucleus. Huntingtin may also be involved in
regulating levels of a critical nerve growth factor.
DNA testing can be done to determine whether triplet expansion has occurred
Stem cells being tested as possible therapy
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d. Duchenne Muscular Dystrophy
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X-linked recessive trait
Affects mostly boys at frequency of 1/3500 males
Onset between age 1 and 6
Leads to progressive muscle weakness; muscle damage is not repaired and is
replaced by fat
Affected individuals are wheelchair bound by age 12
Death usually occurs by age 20.
Due to defect in dystrophin gene, a very large gene in the middle of the short arm
of the X-chromosome (Xp21)
Function of normal dystrophin protein is to stabilize the plasma membrane during
muscle contraction. It attaches to proteins in the cytoplasm to anchor the
membrane
Both Duchenne Muscular Dystrophy, and a milder disease, Becker Muscular
Dystrophy are due to defects in the dystrophin gene.
DMD patients usually have a large deletion that leads to formation of a shortened
protein. BMD patients usually have less severe mutations and produce a partially
functional protein
e. Cystic Fibrosis
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Autosomal recessive trait
Frequency of 1/2000 births in U.S. Caucasian population. Carrier frequency is
1/22 in same group.
Leads to accumulation of mucus in lungs and pancreas and causes male sterility.
Diagnosed in newborns by salty sweat.
Due to defect in gene on Chromosome 7 for CFTR (cystic fibrosis transmembrane
conductance regulator).
Gene isolated by Lap-chee Tsui and Francis Collins in 1989 using positional
cloning methods.
CFTR is a membrane protein that regulates the flow of choride ions across the
plasma membrane.
The most common defect (~70% of cases) is a 3 bp deletion at amino acid 508 of
a phenylalanine residue (Δ508).
Focus on for final exam:
 Multiple choice questions will be based on the diseases PKU, sickle cell anemia,
HD, DMD and CF
 There will also be a short answer essay question asking you to describe a
particular genetic disease of your choice in terms of its symptoms, cause,
diagnosis, mode of inheritance, treatment, and ethical issues. With the exception
of X-linked disorders, you need not recall the chromosomal location of the
disease gene.
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