Molecular and Biochemical Genetics

From Iusmgenetics

Contents 1 Molecular and Biochemical Genetics 1.1 Objectives 1.2 Review your fundamentals 1.3 Dominant Diseases 1.3.1 Achondroplasia 1.3.2 Osteogenesis imperfecta 1.3.3 Ehlers Danlos Syndrome 1.3.4 Marfan syndrome 1.3.5 Familial Hypercholesterolemia 1.4 Recessive Diseases 1.4.1 Homocysteinuria 1.4.2 Cystic Fibrosis 1.4.3 Hemochromatosis 1.4.4 Alpha-1-Anti-Trypsin deficiency 1.5 X-linked Diseases 1.5.1 Rett Syndrome 1.5.2 Lesch-Nyhan syndrome 1.5.3 Inherited Muscular Dystrophies

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-negatie 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 we describe 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

X-linked Diseases

Rett Syndrome

Lesch-Nyhan syndrome

Inherited Muscular Dystrophies