Lecture 2 and 3 2023 Genetic diseases I PDF

Genetic variation A mutation is defined as a stable, heritable change in DNA. Definition does not depend on the functional significance of the change. It implies a change in primary nucleotide sequence. Other changes, such as those involving methylation, are usually refe...

Genetic variation A mutation is defined as a stable, heritable change in DNA. Definition does not depend on the functional significance of the change. It implies a change in primary nucleotide sequence. Other changes, such as those involving methylation, are usually referred to as epigenetic events. Mutations are quite diverse in nature Some involve gross alterations (millions of base pairs) in the structure of a chromosome; duplications - deletions - translocations of a portion of one chromosome to another. Mutations can even involve the entire genome (three billion base pairs), as in triploidy, where there is a third copy of the whole chromosome complement. Mutations can also be minute, involving a deletion, insertion, or replacement of a single base. Single-base or very small mutations are called point mutations. If deletions or insertions of one or two bases occur in a coding region = frame shift mutations à Frame shift mutations grossly alter the protein Small deletions or insertions can also affect transcription, splicing, or RNA processing, depending on their location. When one base is replaced by another in the coding region, the point mutations are common type of pathogenic change: Missense mutations Nonsense mutations Splicing mutations Frame shifts Promoter mutations Pathogenic synonymous or silent mutations A base substitution in the coding region could alter RNA splicing either by (1) creating a cryptic splice site (e.g., hemoglobin E) (2) interfering with the function of a normal splice site (e.g., the R560T mutation in cystic fibrosis). For missense mutations, the single-letter amino acid code is often used to indicate substitutions, such that R560T indicates replacement of arginine (R) at position 560 by threonine (T). Missense Mutation: The sickle-cell mutation (Aà T) A ->T mutation in the β-globin gene causes an a.a. change from glutamic acid, a hydrophilic charged a.a., to valine a hyrophobic nonpolar a.a. end result aggregation hemoglobin molecules distorting red blood cells Nonsense mutations and nonsense-mediated decay PAX3 gene SOX10 Mutations in red escape NMD results in a more severe pheotype  Mutations that affects splicing Disrupt splicing CFTR gene Cryptic splice site Highly expressed Inactivation of splicing enhancer Not expressed TTT and TTC are both phenyalanine (F), TTT Inactivates splicing enhancer  Mutations that affects the reading frame A frame shift Two globin mutations that cause Thalassemia β-globin α-globin Resulting protein has 31 additional a.a. which is unstable and causes α-thalassemia  Variations in an intron of the CFTR gene affect splicing > Variations in an intron of the CFTR gene affect efficiency of splicing. > interestingly, not pathogenic except in association with a coding variant such as p.R117H (lowers activity)  Dynamic Pathogenic Mutations Fragile X Myotonic dystrophy Huntington  GENETIC DISEASES FREQUECY OF about 5% of live born may take the form of single-gene or monogenic defect mitochondrial disorder chromosomal disorders multifactorial disorders common diseases of later life, perhaps up to two-thirds, have a genetic component Databases of Human Genetic diseases 1. OMIM www.ncbi.nlm.gov/omim 2. The genetic association database www.geneticassociationdb.nih.gov 3. Genecards www.genecards.org 4. GeneTests www.geneclinics.org  Single-gene defects Affected gene is located on the X chromosome or one of the 22 autosomes. The trait recessive or dominant There is a 5000 monogenic diseases.. This represents a significant fraction of the total number of human genes, estimated to be between 30000 and 35000 Single-gene disorders that are both severe and relatively common are known as major disorders  Mendelian Pedigree Patterns Main Symbols used in pedigree They can be be : autosomal recessive autosomal dominant X-linked recessive X-linked dominant  Autosomal recessive disorders Both parents are asymptomatic carriers or heterozygous. It affects either sex. There is an increased incidence of parental consanguinity Examples: 1. cystic fibrosis in European populations 2. Sickle cell anaemia and thalassaemias in Asian & Africa populations 3. Tay-Sachs in Ashkenazi Jews/French Canadians  Autosomal recessive disorders Heterozygotes may enjoy some advantage, resulting in the allele frequency being elevated by selection à sickle cell anaemia and thalassaemias are more resistant to malaria Ethnic origin of a patient may be relevant in arriving at a correct diagnosis Pedigree pattern of an autosomal recessive condition  Cystic fibrosis Gene encodes a protein : cystic fibrosis transmembrane conductance regulator (CFTR) transports chloride ions across membrane. water molecules follow ions because of osmosis, insufficient water is secreted onto the cell surface.. àà results in a thick and sticky mucus causing congestion in the lung airways and repeated bacterial infections The pancreatic duct may become blocked, resulting in digestive difficulties. this is known as pancreatic exocrine deficiency  Haemoglobinopathies Sickle cell anaemia, α and β thalassaemias and glucose-6-phosphate dehydrogenase deficiency causing a class of disease known as haemoglobinopathies Ingram (1956) demonstrated that sickle cell anemia results from a single-base mutation affecting the gene encoding β- globin (one amino acid difference) à 1st evidence that sequence of amino acid in Vernon M. Ingram (1924-2006) proteins is determined by genes.  Sickle cells Erythrocytes deformed by hemoglobin S Normal blood smear Sickle cells Blood smear at sickle crisis  Sickle Cell Anemia Consequences of a mutation à Sickle Cell Anemia Selective advantage of HbS heterozygotes à Malaria Carriers are more resistant to Malaria à selection for the mutation and consequently an increased occurrence of the recessive homozygotes who suffer from the disease. = balanced polymorphism  Lysosomes and LSDs Yan G. Zhao, and Hong Zhang J Cell Biol  Tay-Sachs Disease Warren Tay and Bernard Sachs, two physicians of the late 19th century, were the first to describe the disease and provided differential diagnostic criteria to distinguish it from other neurological disorders with similar Bernard Sachs (1858-1944) Waren Tay (1843-1927) symptoms. Tay reported his observations in 1881 in the first volume of the proceedings of the British Ophthalmological Society, of which he was a founding member. Bernard Sachs, an American neurologist, reported similar findings when he reported a case of "arrested cerebral development" to members of the New York Neurological Society. Both Tay and Sachs reported their first cases among Jewish families.  Tay-Sachs Disease An autosomal recessive disease. High incidence among Ashkenazi Jews. Most common mutation is a four base pair insertion in exon 11 (1278insTATC) Onset at 5-9 months of age with progressive psychomotor deterioration. A deficiency of the a subunit of hexosaminidase A. Average life span is 3-5 years. Accumulations of GM2 gangliosides in CNS.  Forms of Tay Sachs disease Infantile Tay–Sachs disease. The child may become blind, deaf, unable to swallow and paralytic.life span about 4 yrs. Juvenile Tay–Sachs disease. People with Tay–Sachs disease develop congitive and motor skill deterioration. Life span between five to fifteen years. Adult/Late-Onset Tay–Sachs disease: characterized by progressive neurological deterioration. Symptoms of late-onset Tay–Sachs include speech and swallowing difficulties, cognitive decline, and psychiatric illness leading to psychosis. Patients late-onset Tay–Sachs may become wheelchair-bound. Journalist Amanda Pazornik describes the experience of one family: "Payton was a beautiful baby girl — but she would not sit up. Four months passed, and similar milestones seemed to slip away. She wouldn't roll over. She wouldn't play with her toys. She still wouldn't sit up. Payton's symptoms progressively worsened. Loud noises inexplicably startled her. An inability to coordinate muscle movement between her mouth and tongue caused her to choke on food and produce excessive saliva." Payton died in 2006 at the age of 3½. Why is the TSD mouse model asymptomatic? Glucose Galactose GM1 Cer GalNAc Sialic Acid 1 b-Galactosidase 1 (GM1 gangliosidosis) 2 Hexosaminidase A GM2 Cer (Tay-Sachs) 3 3 Sialidase (Sialidosis) 2 4 Hexosaminidase B (Sandhoff) GM3 Cer Cer GA2 3 4 LacCer Cer 1 GluCer Cer Catabolism of GM2 gangliosides via GM3 in humans (1à2à3à1) or via GA2 in mouse (1à3à4à1). Cer, ceramide.