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Genetic Disorders Genes and Human Disease Mutation o Permanent change in the DNA sequence Somatic cell mutation:

n: May progress to cancer Germ cell mutation: Gives rise to inherited disease o Caused by: Mutagens from the environment Errors in DNA replication and proofreading o Categories: Category Mendelian Disorders Chromosomal Disorders Complex Multigenic Disorders Prevalence Uncommon Uncommon Penetrance High High Defect Single Gene Chromosome structure/ function Polymorphisms



o Types of Mutation Substitution Deletion Insertion o General Principles of the Effects of Gene Mutations Point mutations within coding sequences: one base is substituted for another. Missense mutations: alters the code in a triplet of bases and lead to the replacement of one amino acid by another in the gene product o Conservative: If the substituted amino acid causes little change in the function of the protein o Non-conservative: replaces the normal amino acid with a very different one Nonsense mutations: changes an amino acid codon to a chain terminator, or stop codon o Leads to premature termination of translation o The short peptide that is produced is rapidly degraded Silent Mutations: alteration in a DNA sequence that does not result in an amino acid change in a polypeptide

Deletions and Insertions Frameshift mutation, involvement is NOT a multiple of 3

Trinucleotide Repeat Mutations Amplification of a sequence of three nucleotides Dynamic (degree of amplification increases gametogenesis) Effects of Mutation o Interfere with protein synthesis o Suppress transcription, DNARNA o Produce abnormal mRNA o Defects carried over into translation o Abnormal proteins without impairing syntheses o But uncommonly, may be beneficial


Mutations within Non-coding Sequences Defective transcription Defective splicing of intervening sequences.

Mendelian Disorders Autosomal Dominant Disorders o Heterozygous state o Neither parent may have the disease (new mutations involving the gametes) o Reduced Penetrance o Variable Expressivity o Delayed onset (i.e. Huntingtons disease) o Usually result in a reduced production or inactive protein System Disorder Nervous Huntingtons Disease Neurofibromatosis Myotonic Dystrophy Urinary Gastrointestinal Hematopoietic Skeletal Tuberous sclerosis Polycystic kidney disease Familial polyposis coli Hereditary spherocytosis Von Willebrand Disease Marfan Syndrome


Ehlers-Danlos Syndrome (some variants) Osteogenesis Imperfecta Achondroplasia Familial Hypercholesterolemia Acute intermittent porphyria

Autosomal Recessive Disorders o Most common o Include almost all inborn errors of metabolism o More uniform expression than in AD o Often complete penetrance o Onset usually early in life o New mutations rarely detected clinically o Many of the mutated genes encode enzymes o Proteins show loss of function System Disorders Metabolic Cystic fibrosis PKU Galactosemia Homocystinuria Lysosomal Storage Diseases 1 Antitrypsin Deficiency Wilson Disease Hemochromatosis Hematopoietic Endocrine Skeletal Nervous Glycogen Storage Diseases Sickle Cell Anemia Thalassemias Congenital Adrenal hyperplasia Ehlers Danlos Syndrome (some variants) Alkaptonuria Neurogenic Muscular Atrophies Friedreich Ataxia Spinal Muscular Atrophy

X-Linked Disorders o All sex-linked disorders are X-linked Males with mutations in the Y gene are infertile Cannot be passed to succeeding generations o Almost all are recessive o The Y chromosome is NOT homologous to the X, i.e., the concept of dominant/recessive has no meaning here System Disease Musculoskeletal Blood Duchenne muscular dystrophy Hemophila A and B Chronic granulomatous disease G6PD deficiency Agammaglobulinemia Wiskott-Aldrich Syndrome Diabetes Insipidus Lesch-Nyhan Syndrome Fragile X syndrome

Immune Metabolic Nervous