Chapter 5 - Genetic Disorders Flashcards
Three broad categories of human genetic disorders
- Mutations in single genes with large effects (Mendelian disorders)
- Chromosomal disorders
- Complex multigenic disorders
*4. Single-gene disorders with nonclassic patterns of inheritance
Mutation definition
A permanent change in DNA. Mutations that affect germ cells are transmitted to the progeny and give rise to inherited disease.
General principles of gene mutation: Point mutations within coding sequences
Change in a single base (substituted for another base) - this may alter gene product by coding a different amino acid (i.e. missense mutation)
- Conservative missense mutation - similar protein, minimal functional deficit
- Nonconservative missense mutation - different protein (e.g. sickle mutation in b-globin)
- Nonsense mutation - when the bvase change results in a stop codon (e.g. B0-thalassemia)
General principles of gene muation: Mutations within noncoding sequences
Recall: DNA transcription is initiated / regulated by promoter and enhancer sequences.
Point mutations or deletions in these sites may interfere with binding of transcription factors and lead to decreased transcription
Point mutations in introns can also disrupt splicing and lead to decreased transcription
General principles of gene mutations: Deletions and insertions
- Small D and Is involving hte coding sequence can have 2 possible effects:|
(1) If the # of base pairs involved is a multiple of 3, reading frame is intact, abnormal protein +/- one or more AA
(2) If # of affected base pairs is not a multiple of 3, it’s a frameshift mutation; variable # of incorrect AAs until a random stop codon (e.g. Tay-Sachs)
General principles in gene mutations: Trinucleotide-repeat mutations
- Amplification of a sequence of three nucleotides
- Specific sequence that repeats varies in different disorders, but almost all share C and G nucleotides
(e. g. Fragile X syndrome) - These mutations are dynamic (amplifications increase during gametogenesis)
Pleiotropism vs. genetic heterogeneity
Pleiotropism - a mutant gene may lead to a number of end effects (e.g. sickle cell mutation -> anemia, splenic fibrosis, organ infarcts, bone changes)
Genetic heterogeneity - Mutations at several genetic loci may each produce the same trait (e.g. profound childhood deafness may result from many different autosomal recessive mutations)
Mutations involving single genes typically follow one of these three patterns of inheritance:
- Autosomal dominant
- Autosomal recessive
- X-linked
Groups of single gene disorders with nonclassic inheritance
- Diseases caused by trinucleotide repeat mutations
- Disorders caused by mutations in mitochondrial genes
- Disorders associated with genomic imprinting
- Disorders associated with gonadal mosaicism
Autosomal dominant disorders
These are manifested in heterozygous state; 1+ parent is usually affected.
Progeny of 1 affected and 1 unaffected parent has 50% chance of disease
Some patients do not have affected parents (due to new mutations in egg or sperm)
Clinical features can be modified by variations in penetrance and expressivity
- Incomplete penetrance: patient gets mutant gene, but is normal
- Variable expressivity: All patients with mutant gene have the disease, but with varying severities
Many autosomal dominant diseases arising from deleterious mutations fall into one of a few familiar patterns:
- Those involved in regulation of complex metabolic pathways that are subject to feedback inhibition (e.g. familial hypercholesterolemia - LDL receptors are lost by 50% in heterozygotes –> predisposed to atherosclerosis)
- Key structural proteins, such as collagen and cytoskeletal elements of RBCs (spectrin)
Autosomal recessive disorders
These make up the largest cateogry of Mendelian disorders. They can occur when both alleles at a given locus are mutated.
Features of autosomal recessive disorders:
(1) The trait does not usually affect the parents, but siblings may show disease.
(2) Siblings have 1/4 chance of having the trait
(3) If the mutant gene occurs with a low frequency in the population, there is a strong likelihood that the affected individual is the product of incest.
Features that distinguish auto. reces. disorders from auto. dom:
(1) Expression of defect is more uniform
(2) Complete penetrance is common
(3) Onset is early in life
(4) New mutations are rarely detected
(5) Many mutated genes code enzymes
X-linked disorders
All sex-linked disorders are x-linked, and almost all are recessive.
- These are seen in hemizygous males
- Affectged males do not give it to son, but all daughters are carriers
- Heterozygous females usually do NOT have the disease, but may have partial disease
- Dominant, x-linked disease is rare, affected heterozygous mom gives it to half her sons and half her daughters; affected dad gives it to all daughters and no sons
KEY CONCEPTS: Transmission patterns of single-gene disorders
Four categories of mechanisms involving single-gene mutations
- Enzyme defects and their consequences
- Defects in membrane receptors, transport systems
- Alterations in structure, function, quantity of non-enzyme proteins
- Mutations resulting in unusual drug reactions
Three major consequences that are possible with single-gene mutations affecting enzymes:
- Accumulation of the substrate and/or intermediates (e.g. galactosemia - defic. in galactose-1-phosphate uridyltransferase)
- A metabolic block, and decreased amount of end product (e.g. albinism - melanin deficiency due to lack of tyrosinase)
- Failure to inactivate a tissue-damaging substrate (e.g. a1-antitrypsin deficiency –> decrease in neutrophil elastase in lungs –> unchecked protease activity –> emphysema)
A possible metabolic pathway in which a substrate is converted to an end product by a series of enzyme reactions. M1, M2, products of a minor pathway.
Disorders associated with defects in structural proteins: Marfan Syndrome
A Mendelian disorder of connective tissue manifested principally by changes in the skeleton, eyes, and cardiovascular system, resulting from an inherited defect in an extracellular glycoprotein fibrillin-1.
Lack of fibrillin-1 –> loss of structural support in microfibril-rich CT AND excessive activation of TGF-b signaling
> 600 mutations in FBN1 result in decreased normal fibrillin-1 levels and clinical Marfan syndrome
Disorders associated with defects in structural proteins: Ehrlos-Danos Syndrome
EDSs comprise a clinically and genetically heterogeneous group of disorders that result from some defect in the synthesis or structure of fibrillar collagen.
- Caused by genetic errors affecting one of the structural collagen genes or an enzyme necessary for post-translational modification
Collagen-rich tissues mostly affected (skin, ligaments, joints)
Skin is hyperextensible, joints are hypermobile (Dachshunds)
KEY CONCEPTS: Marfan and Ehrlos Danos Syndromes
Disorders associated with defects in receptor proteins: Familial hypercholesterolemia
“Receptor disease” that is the consequence of a mutation in the gene encoding for the LDL receptor, which is involved in the transport an dmetabolism of cholesterol.
Low-density lipoprotein (LDL) metabolism and the role of the liver in its synthesis and clearance. Lipolysis of very-low-density lipoprotein (VLDL) by lipoprotein lipase in the capillaries releases triglycerides, which are then stored in fat cells and used as a source of energy in skeletal muscles. See text for explanation of abbreviations used.
The LDL receptor pathway and regulation of cholesterol metabolism.
Classification of LDL receptor mutations based on abnormal function of the mutant protein. These mutations disrupt the receptor’s synthesis in the endoplasmic reticulum, transport to the Golgi complex, binding of apoprotein ligands, clustering in coated pits, and recycling in endosomes. Each class is heterogeneous at the DNA level.
