Transcript Single-gene Autosomal Disorders

Single-gene Autosomal Disorders
Basic terminology
Genotype: A A
B
(Heterozygous)
(Homozygous)
A
B
A
Gene
Chromosome 6
Maternal copy
DNA
Chromosome 6
Paternal copy
Single gene disorder - determined by the alleles at a single locus
Reminder
• Autosomes
– Chromosomes 1-22
– An individual inherits one chromosome from each parent
– An individual therefore inherits a paternal copy and a
maternal copy of an autosomal gene
• Sex chromosomes
– X and Y
– A female inherits an X from their mother and an X from
their father
– A male inherits an X from their mother and the Y from their
father
Autosomal Recessive disorders
• Cystic fibrosis
• Tay sachs
• Phenylketonuria
Cystic fibrosis (CF) - an autosomal recessive
disease
• Diseased homozygotes: ~30,000 in the U.S.
– 1/3500 births
• Carriers (heterozygotes): ~1/25-30
• Caused by mutations in the cystic fibrosis
transmembrane conductance regulator gene (CFTR)
on chromosome 7.
• Clinical symptoms include pancreatic insufficiency
and pulmonary infections
CFTR function
Regulates the flow of chloride ions
across the cell membrane
paternal
maternal
A
a
A
AA
Aa
1/4 unaffected non-carrier
a
Aa
aa
1/2 unaffected carrier
1/4 affected
Tay-Sachs Disease lysosomal storage disease
Tay-Sachs Disease
normal
GM2 ganglioside
GM2 ganglioside
hexosaminidase A
hexosaminidase A
degradation
products
removal/ recycling of
sphingolipid components
GM2 ganglioside
accumulates in
the lysosomes
Neurodegeneration
Tay-Sachs: the clinical picture
• Infants
with Tay-Sachs appear normal until about
3 to 6 months of age
• Motor development plateaus by 8-10 months
• loss of all voluntary movement by 2 yrs
•Worsening seizures
• difficulty swallowing
• vegetative, unresponsive state
• Patients almost always die by 2 to 4 years of
age.
• There is no cure, and no effective treatment.
Tay-Sachs disease:
Autosomal recessive disorder
Rare in some populations and common in others.
Frequency of Tay-Sachs is about:
1/360,000 live births for non-Ashkenazi North Americans, and
1/3600 for North American Ashkenazi Jews
Carrier frequencies are therefore about:
1/27 Jews in the U.S.
Cajuns have the same rate.
Disease and carrier frequencies in some other ethnic groups (French
Canadians, Louisiana Cajuns, and Pennsylvania Amish) are comparable to
those seen among Ashkenazi Jews.
PKU
• Body cannot produce enzyme phenylalanine
hydroxylase (PAH).
• Results in an accumulation of phenylalanine,
which hinders brain development, causing
mental retardation.
Autosomal Dominant
• Huntington’s Disease
• Neurofibromatosis
• Marfan syndrome
Huntington’s Disease
• Causes degeneration of nerve cells in the brain.
• Onset of symptoms usually begins in 40s and 50s, after
a person has had children.
• Medications can be prescribed to manage symptoms,
but there is no treatment for the disease itself.
• Symptoms include trouble moving, cognitive problems,
depression, etc.
• Death occurs 10-30 years after the onset of symptoms.
• Affects 5 out of 100,000 people.
Huntington’s Disease
Neurofibromatosis
• Caused by a mutation in
a tumor suppressor
gene.
• Results in tumors all
over the body.
Neurofibromatosis
• Affects 1 in 2500-3000 births
• In many cases, symptoms are milder.
Marfan Syndrome
• Affects about 1 in 5000 people
• Caused by a mutation in the FBN1 gene, which
encodes the protein fibrillin-1, a protein found
in connective tissue.
• Problems result related to connective tissue
such as that found in bone, heart, and
vascular tissue.
Marfan syndrome symptoms
•
•
•
•
•
•
•
Tall
Enlarged aorta
Other heart problems
Long arms and legs, long fingers
Curvature of the spine
Sudden collapse of the lung
If treated, people with Marfan syndrome have
a close-to-average lifespan.
Marfan Syndrome