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Transcript
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