Molecular and Biochemical Genetics

From Iusmgenetics

Revision as of 22:27, 12 December 2011

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:

• 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:
    • Phenylketonuria
    • Galactosemia
    • Maple Syrup Urine Disease
    • Homocysteinuria
    • Biotinidase Deficiency
  • Endocrine disorders:
    • Hypothyroidism
    • Congenital Adrenal Hyperplasia
  • Hemoglobinopathies:
    • Sickle Cell Disease
  • Cystic Fibrosis
• Using several methods: enzyme assays, radiommunoassays, electrophoresis, tandem bass 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.
• Procedures prompted by screening can 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