Genetic Disorders and Mutations

Genetic Disorders

• Definition: Diseases that are caused in whole or in part by a change in the DNA sequence.

Types of Genetic Disorders

• Monogenic: Disorders caused by a mutation in a single gene.

• Multifactorial Inheritance Disorder: Disorders caused by mutations in multiple genes.

• According to the NIH National Human Genome Research Institute, nearly all diseases have a genetic component.

Inheritance of Disease-causing Mutations

• Inherited Mutations:
    - Disease-causing mutations can be inherited from parents to offspring and are present at birth.
    - Example: Sickle Cell Disease.

• Acquired Mutations:
    - Occur throughout a lifetime due to:
      - Random mutations.
      - Environmental exposures (e.g., cancer).

Mutations: Changes in the Genetic Code

• Definition: A change in the genotype (the nitrogen base sequence of DNA) is referred to as a mutation.

• Categories of Mutations:
    - Point Mutation: Addition, deletion, or substitution of a few bases.
      - Missense Mutation: Causes a change in a single amino acid.
      - Nonsense Mutation: Changes a normal codon into a stop codon.
      - Silent Mutation: Alters a base but does not change the amino acid.
      - Frameshift Mutation: Alters the reading frame of the mRNA.

Point Mutations and Their Effects

• Types of Point Mutations:
    - No mutation:
      - DNA Level: TTC (No mutation)
    - Silent:
      - DNA Level: TTT
      - mRNA Level: AAA
      - Protein Level: Lys
    - Nonsense:
      - DNA Level: TGC
      - mRNA Level: UGC
      - Protein Level: Stop
    - Missense:
      - Conservative Missense:
        - DNA Level: ATC
        - mRNA Level: UAG
        - Protein Level: Arg
      - Non-conservative Missense:
        - DNA Level: TCC
        - mRNA Level: AGG
        - Protein Level: Thr

Frameshift Mutations

• Example Frameshift:
    - Original Sequence: AGCGUACCCUAC-
      - Protein Sequence: Ser Val Pro Tyr
    - Mutated Sequence: AGCGCCCUACUU
      - Protein Sequence: Ser Ala Leu Leu

Repair of Mutations

• Cells have several enzymatic repair mechanisms in place to locate and repair damaged DNA due to the potential fatal consequences of mutations:
    - DNA Polymerase: Proofreads nucleotides during DNA replication.
    - Mismatch Repair: Locates and repairs mismatched nitrogen bases that were not repaired by DNA polymerase.
    - Excision Repair: Locates and repairs incorrect sequences by removing a segment of the DNA and adding the correct nucleotides.

Positive and Negative Effects of Mutations

• Negative Effects:
    - Mutations that result in nonfunctional proteins can be harmful and potentially fatal.

• Positive Effects:
    - Beneficial mutations allow organisms to adapt, survive, and reproduce. These beneficial mutations drive change in populations.
    - Any change that confers an advantage during selection pressure will be retained by the population.

Specific Genetic Disorders

• Cystic Fibrosis:
    - The most common fatal genetic disease in the U.S.
    - Caused by mutations in the CFTR (Cystic Fibrosis Transmembrane Regulator) gene.
    - Over 900 mutations of this gene identified.
    - People with CF cannot release chloride, leading to improper salt balance and the production of thick, sticky mucus.
    - Symptoms: Salty skin, persistent cough, poor weight gain.
    - Effects: Sticky mucus clogs the lungs causing infection and blocks the pancreas.
    - Statistics: 1 in 31 Americans are carriers of a CFTR mutation; if two carriers have a child, the child has a 25% chance of having CF.

• Huntington’s Disease:
    - Inherited neurological disorder causing involuntary movements.
    - Results from a mutated gene on chromosome 4 (HTT).
    - Defective gene has excessive repeats of CAG (typically 11-29 times; HD 40-80+ times).
    - Causes a malformed protein that clumps in the brain, killing nerve cells.
    - Dominantly inherited: inheriting one copy is sufficient to cause the disease.
    - Ongoing research to find drugs that control symptoms and slow disease progression.

• Hemophilia A:
    - Also known as classic hemophilia.
    - Caused by mutations in the FVIII (F8) gene, which is X-linked recessive.
    - Codes for a protein essential for blood clotting (clotting factor 8).
    - Symptoms: Long bleeding after an injury or surgery; easy bruising; severe cases may involve spontaneous bleeding in joints, bowel, or brain.
    - Statistics: 1 in 5,000-10,000 males worldwide have Hemophilia A.
    - Treatment: Depends on severity, includes clotting factor infusions and treatment with a medicine called desmopressin.

• Down Syndrome:
    - A chromosomal condition characterized by three copies of chromosome 21.
    - Occurs in approximately 1 in 800-1000 live births.
    - Can lead to various health issues, including heart defects, digestive problems, hypothyroidism, hearing loss, and learning difficulties.
    - Characteristic facial appearance often observed.
    - Mostly non-inherited; caused by random events during reproductive cell formation.