Molecular and Biochemical Genetics
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Contents |
Molecular and Biochemical Genetics
Objectives
- Important terms:
- "Incomplete" dominance or "semi-dominant": homozygous individuals have a worse manifestation than heterozygous individuals (achondroplasia).
- "Distinct disorder": consistent clinical and radiological findings.
- Important concepts:
- Types of mutations:
- Missense: changed amino acid
- Nonsense: introduced stop codon
- Neutral / silent: no amino acid change
- Polymorphisms are a population term; it means 1% of the pop has it; it does not infer whether it causes disease or not
- RNA splicing: gain or loss of splice site
- Regulation mutation: affects gene regulation
- Indels: gain or loss of one or more bases; leads to frameshift if not a multiple of 3
- Repeat expansion: repeated segment (usually 3 bases) expands as nucleotide copy / repair mechanisms get hung up
- Haploinsufficiency:
- Dominant-negative effect:
- Types of mutations:
- For individual diseases, know: clinical features, mode of inheritance, genes involved / gene defect, pathogenesis, treatment (sometimes)
Review your fundamentals
Dominant Diseases
- Dominant disease are defined as those manifested when only one allele is mutated.
- Recall that some diseases can be both dominant and negative because of allelic heterogeneity and locus heterogeneity.
- There are multiple ways a single allele (not both copies) can cause disease:
- Qualitative effects: the protein product gains a function.
- Quantitative effects: the protein product is broken.
- Combination of qualitative and quantitative.
- Others
- It is important to understand the disease pathogenesis in order to think wisely about treatment.
Achondroplasia
Osteogenesis imperfecta
Ehlers Danlos Syndrome
Marfan syndrome
Familial Hypercholesterolemia
Recessive Diseases
- Requires two mutant alleles to show the phenotype or disease state.
- Recall that a proband with a recessive disease usually has parents who are both carriers.
- However, there are exceptions: uniparental disomy, skewed lyonization.
- Recessive disorders usually result from a missing component of a pathway.
- Phenotype usually results from the accumulation of a precursor / metabolite.
Homocysteinuria
Cystic Fibrosis
Hemochromatosis
Alpha-1-Anti-Trypsin deficiency
Phenylketonuria
Tay-Sachs Disease
Galactosemia
Maple Syrup Urine Disease
Biotinidase Deficiency
X-linked Diseases
Rett Syndrome
Lesch-Nyhan syndrome
Inherited Muscular Dystrophies
Newborn Screening
- The following criteria for newborn screening assure that our screening has analytic validity, clinical validity, and clinical utility:
- The disorder must be well defined.
- The disorder must be fairly high in population frequency (to justify the cost of newborn screening by the cost saved in care for the true-positives).
- The disorder must be poorly clinically detected early in life (assymptomatic) (otherwise it is more cost effective to let physicians identify the disease at newborn checkups).
- The disorder must be significant in morbidity / mortality if left untreated (otherwise we might start treating things that have little consequence).
- The disorder must be treatable such that there is an improved condition (lest we start adding anxiety to insult).
- The test must be rapid, inexpensive, specific AND sensitive over an entire population.
- The test must be acceptable and cost-effective.
- The test must be appropriately administered.
- Newborn screening is required by law on all infants
- A second test is required if the first screen is done prior to 48 hours
- In Indiana we screen for:
- Metabolic disorders:
- Endocrine disorders:
- Hypothyroidism
- Congenital Adrenal Hyperplasia
- Hemoglobinopathies:
- Sickle Cell Disease
- Cystic Fibrosis
- Using several methods: enzyme assays, radiommunoassays, electrophoresis, tandem mass spectrometry
Pitfalls of Screening
- False positives cause unecessary stress / anxiety and investigation / treatment.
- False negatives cause false security.
- Recalling the requirement that a screened disease must be "treatable" in some effective way, we see that prolonging the knowledge of a disease may be a form of harm if the disease cannot be treated.
- Medical procedures initiated because of screen results may be uncomfortable and unnecessary.
General Molecular / Biochemical Pathogenesis Principles
- Dominant diseases usually result from:
- Gain of abnormal function
- Haploinsufficiency
- Dominant-negative effects (think multi-subunit proteins)
- Combinations of these reasons
- Recall that dominant disease can be "incomplete" and thus have more severe phenotypes when presented as homozygous conditions.
- Recessive diseases usually result from:
- Loss of normal function
- Heterozygotes of recessive diseases (carriers) usually have enough wild-type gene product to function properly.