Etiology of Inherited Disorders

I. Mutagenesis

• Definition: Process of inducing mutations in genetic material

• Types of mutagens:

  • Chemical mutagens (e.g., alkylating agents, base analogs)

  • Physical mutagens (e.g., ionizing radiation, UV radiation)

  • Biological mutagens (e.g., certain viruses)

• Mechanisms of mutagenesis:

  • Point mutations (single base changes)

  • Insertions and deletions (addition or removal of bases)

  • Chromosomal rearrangements (e.g., translocations, inversions)

II. Definition and Classification of Gene Mutations

• Gene mutation: Alteration in the DNA sequence of a gene

• 4 classes

  • spontaneous mutations(molecular decay)

    • Tautomerism-a base is changed by the repositioning of an H atom

    • Depurination- loss of purine base (repair mechanism exists)

    • Deamination- removal of an NH2 group by hydrolysis (NO REPAIR MECHANISM)

  • DNA damage

  • errors induced in DNA repair

  • Mutations caused by mutagens

• Types of gene mutations:

  • Missense mutation: Single base change leading to an amino acid substitution

  • Nonsense mutation: Single base change leading to a premature stop codon

  • Frameshift mutation: Insertion or deletion of bases, altering the reading frame

  • Silent mutation: Single base change without changing the amino acid sequence

  • Splice site mutation: Alteration in the intron-exon boundary, affecting mRNA splicing

  • Point mutation- changes ti a single nucleotide

  • Deletion- removal of a nucleotide

  • Trinucleotide repeats

  • Transition- replacement with a base from the same group (ex. A-G)

  • Transversions- replacement of a base with one from the other group (ex.A-C)

III. Phenotypic Effect of Mutations

• Loss-of-function mutations: Result in reduced or absent protein function

• Gain-of-function mutations: Lead to abnormal protein function or increased activity

• Dominant-negative mutations: Mutant protein interferes with the function of the normal protein

• Haploid sufficiency: One functional copy of a gene is insufficient to maintain normal function

IV. Large scale mutations

• Amplifications/gene duplications- multiple copies of all chromosomal regions

• Deletions of chromosomal regions

• Chromosomal rearrangements- translocations and inversions

• Loss of heterozygosity-loss of one of the alleles

SOMATIC vs GERMLINE

Somatic- occur in a single somatic cell and can’t be inherited (only tissues derived from the affected cell are affected)

• occur during mitosis

• caused by both endogenous and exogenous factors

• in most cases show no effect and contribute ti genetic diversity

• can cause cancer -mutation in a proto-oncogene

Germline- occur in gametes and can be passed on ( every cell in the organism will be affected)

• caused by endogenous factors

• occur during meiosis

• ex- haemophilia

• more prominent in the sperm that in oocytes since spermatocytes go through a larger number of cell divisions