Single-gene Autosomal Disorders

Basic terminology Genotype: A A (Homozygous)A A Genotype: A B (Heterozygous)A B Single gene disorder - determined by the alleles at a single locus Chromosome 6 Maternal copy DNA Gene Chromosome 6 Paternal copy

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

AA Aa A a 1/4 unaffected non-carrier 1/2 unaffected carrier Aa Aa aa 1/4 affected maternal p a t e r n a l

Tay-Sachs Disease lysosomal storage disease normal Tay-Sachs Disease G M2 ganglioside hexosaminidase A G M2 ganglioside hexosaminidase A removal/ recycling of sphingolipid components G M2 ganglioside accumulates in the lysosomes degradation products 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. Disease and carrier frequencies in some other ethnic groups (French Canadians, Louisiana Cajuns, and Pennsylvania Amish) are comparable to those seen among Ashkenazi Jews. 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.

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 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 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