11: Molecular & Biochemical Basis of Disease Flashcards
What is allelic heterogeneity?
The occurrence of more than one allele at a locus.
Different mutations at the same locus cause similar disease phenotypes.
E.g., cystic fibrosis: 1,000+ mutations in CFTR can result in disease.
What is locus heterogeneity?
The association of more than one locus with a specific clinical phenotype.
A phenotype caused by mutations in genes at different loci.
E.g., hyperphenylalanemia: caused by mutated phenylalanine hydroxylase (classic PKU) or mutation in gene for BH4 cofactor.
What is clinical/phenotypic heterogeneity?
The association of more than one phenotype with mutatins a a single locus.
Different mutations in a single gene lead to varied phenotypes.
E.g., phenylalanine hydroxylase mutation can cause PKU, variant PKU, or non-PKU hyperphenylalanemia
Describe loss-of-function mutations.
- Account for 90% of mutations
- Results in haploinsufficiency
- Often autosomal recessive
- Tay Sachs
- Cystic fibrosis
- 50% of normal activity is sufficient (thus, carriers are unaffected)
- Majority of inborn errors of metabiolism
What are the characteristics of enzyme deficiencies?
- Enzymopathies are almost always recessive
- Leads to either:
- Substrate accumulation (shunted down toxic alternative pathway)
- Product deficiency
- Loss of multiple enzyme activities
- Phenotypic homology
What are the treatment priniciples for inborn errors of metabolism?
- Dietary modification
- Control of endogenous production of substrate
- Vitamins and cofactors
- Enzyme replacement
- Transplant
What is hyperphenylalaninemia?
- Mildly or strongly elevated levels of the amino acid phenylalanine in the blood.
- Autosomal recessive condition
- Phenylalanine necessary for making tyrosine, dopamine, serotonin, norepinephrine; in these IEOMs, these products are not being produced.
What is alpha-1 antitrypsin disorder?
- Autosomal recessive condition.
- Different mutations can cause different phenotypes (phenotypic heterogeneity).
- Alpha-1 antitrypsin is a protease inhibitor of elastase.
- Inhibitor not produced –> elastase breaks down elastin in lung –> destruction of alveoli –> COPD
- Most common phenotype is chronic obstructive pulmonary disease (COPD).
- Smoking causes more oxidative stress –> destroys residual anti-trypsin activity –> worse prognosis
- Z/Z mutation: misfolded anti-trypsin can’t get out of hepatocytes (where they are produced) –> hepatocyte damage –> cirrhosis + COPD
- Example of phenotypic heterogeneity
What is Duchenne Muscular Dystrophy?
- Dystrophin anchors protein complex to cell membrane to maintain muscle membrane integrity (links actin to extracellular matrix).
- Severity of dystrophinopathy correlates with protein production (less severe = Becker).
- Example of phenotypic heterogeneity.
- Most often due to gene deletion (60%; 1 exon to whole gene)
What are some autosomal dominant loss-of-function mutations?
- Tumor suppressor genes
- BRCA1&2
- Retinoblastoma
- Familial adenomatous polyposis
- 50% of normal activity sufficient, but loss of second gene results in disease (2-hit hypothesis; recessive on cellular level)
- Due to loss of second, somatic gene during lifetime (inherited almost as if carrier, but will develop somatic mutation during lifetime therefore considered AD).
What is haploinsufficiency?
- 50% of normal activity is NOT sufficient for normal activity; leads to abnormal phenotype
- Example: Maturity onset diabetes of youth (MODY): mutation in 1 allele of glucokinase leads to loss of sensitization to glucose concentrations
- Regulation step lost; incorrectly sensing ambient glucokinase levels; “thermostat set too high”
- Autosomal dominant
- Example: Acute Intermittent Porphyria
- Autosomal dominant
- Asymptomatic until drug is used that decreases heme concentrations (e.g., barbiturates)
- Example: LDL Receptor Deficiency
- 2 WT copies of LDL receptor = normal cholesterol levels
- Obligate mutant heterozygotes = moderately high levels of cholesterol
- Mutant homozygotes = severe levels of cholesterol; heart attacks, coronary disease by late teens
- Example of dose-effect
What is ichthyosis with confetti?
- AD condition where a 2nd hit of mutation reverses it (i.e., cures it): revertant spots
- Mitotic homologous recombination
- Loss of heterozygosity to homozygosity
- Rescues the phenotype
What is a dominant negative mutation (antimorph)?
- Act in opposition to normal gene activity; acts antagonistically (poisons) normal gene product (usually from multimer formation)
- Example: osteogenesis imperfecta
- Autosomal dominant
- Brittle bone disease, lots of fractures
- Collagen composed of 2 alpha-1 strands, 1 alpha-2 strand
- Mutation at glycine –> inability to make tight turns in triple helix of alpha-1
- Deletion –> quantitative problems (not enough collagen): Type I OI
- Missense –> qualitative problems (abnormal collagen); this is WORSE, because more collagen affected (75% of fibers “poisoned”): Type I, II, III or IV OI
What is a gain-of-function mutation?
- Change to the gene product such that it gains a new and abnormal function; overly expressed or new function; dominant negative effect
- Example 1: Huntington’s Disease
- CAG polyglutamine repeat –> novel function of gene product –> kills neurons –> brain atrophy
- Larger the repeat size, earlier onset of disease
- Disease presents at earlier age as it is passed down to subsequent generation from father (anticipation) due to repeat expansion
- Example 2: Myotonic Dystrophy
- Expanded repeat affects binding to RNA binding proteins
- Anticipation occurs from mother
- Fish mouth phenotype
- Example 3: Fragile X
- CGG repeat on 5’ UTR
- >200 copies leads to excessive methylation and silences transcription of FMR1 gene
- If 6-200 repeats, **tremor/ataxia syndrome **
- Example 4: Achondroplasia
- Autosomal dominant
- FGFR3 gain of function leads to severe limitation of bone growth
