chapter 12

Chapter 12: Molecular, Biochemical, and Cellular Basis of Genetic Disease

Mutations and Protein Classes

• Organelles:
  • Mitochondria:
  • Mitochondrial Based Diseases:
    • ND1 protein (electron transport chain):
    • Leber Hereditary Optic Neuropathy
    • tRNA leu:
    • MELAS
    • 12S RNA:
    • Sensorineural Deafness
  • Peroxisomes:
  • Peroxisome Biogenesis Disorders:
    • 12 proteins:
    • Zellweger Syndrome
  • Lysosomes:
  • Lysosomal Enzyme Deficiencies:
    • Hexosaminidase A:
    • Tay-Sachs Disease
    • α-L-iduronidase deficiency:
    • Hurler Syndrome

Extracellular Proteins and Related Diseases

• Transport Proteins:
  • ẞ-globin:
  • Sickle Cell Disease
  • B-thalassemia
• Morphogens:
  • Sonic hedgehog:
  • Holoprosencephaly
• Protease Inhibition:
  • α₁-Antitrypsin:
  • Emphysema, Liver Disease
• Hemostasis:
  • Factor VIII:
  • Hemophilia A
• Hormones:
  • Insulin:
  • Rare forms of Type 2 Diabetes Mellitus
• Extracellular Matrix:
  • Collagen type 1:
  • Osteogenesis Imperfecta
• Inflammation & Infection Response:
  • Complement factor H:
  • Age-Related Macular Degeneration

Cytoplasmic and Nuclear Mutations

• Cytoplasm:
  • Metabolic Enzymes:
  • Phenylalanine hydroxylase:
    • Phenylketonuria (PKU)
  • Adenosine deaminase:
    • Severe Combined Immunodeficiency
  • Cytoskeleton:
  • Dystrophin:
    • Duchenne Muscular Dystrophy
• Nucleus:
  • Transcription Factors:
  • Pax6:
    • Aniridia
  • Genome Integrity:
  • BRCA1, BRCA2:
    • Breast Cancer
  • DNA Repair Proteins:
  • Hereditary Nonpolyposis Colon Cancer
  • RNA Regulation:
  • FMRP:
    • Fragile X Syndrome
  • Chromatin Proteins:
  • MeCP2:
    • Rett Syndrome
  • Tumor Suppressors:
  • Rb Protein:
    • Retinoblastoma
  • Oncogenes:
  • BCR-Abl:
    • Chronic Myelogenous Leukemia

Disease Patterns and Mitochondrial DNA

• Characteristics of Mitochondrial DNA Mutations:
  • Replicative Segregation:
  • mtDNA replicates and sorts randomly to new mitochondria.
  • Homoplasmy vs. Heteroplasmy:
  • Affects disease expression based on the percentage of mutated mtDNA.
    • Clinically significant:
    • Over 60% mutated mtDNA leads to disease manifestation.
  • Maternal Inheritance:
  • Mitochondria are inherited from the mother via the egg's cytoplasm.

Representative Mitochondrial Disorders

• Leber Hereditary Optic Neuropathy (LHON):
  • Rapid-onset blindness due to optic nerve atrophy.
  • Strong male bias in severity of symptoms.
• MELAS:
  • Myopathy and stroke-like episodes alongside progressive neurodegeneration.
• MERRF:
  • Myoclonic epilepsy and ragged-red muscle fibers.
• Kearns-Sayre Syndrome (KSS):
  • Progressive external ophthalmoplegia and myopathy.

Treatment of Genetic Diseases

• Levels of Treatment:
  • Intervention on genetic level:
  • Example: Gene therapy for sickle cell disease using CRISPR.
  • Pharmacological modulation:
  • Increase gene expression via drugs (e.g., decitabine for sickle cell).
  • Dietary modifications:
  • Low-phenylalanine diet for PKU.
• Challenges in Treatment:
  • Genetic heterogeneity leads to varied efficacy of treatments.
  • Long-term assessments are necessary for understanding treatment outcomes.

Genetic Heterogeneity in Treatments

• The need for allele-specific treatments, illustrated by cystic fibrosis medications targeting specific mutations (e.g., Kalydeco for specific alleles).

Manipulation of Metabolism

• Strategies for Treatment of Metabolic Disorders:
  • Substrate reduction:
  • E.g., restricting phenylalanine in PKU treatment.
  • Replacement:
  • Hormone supplementation in hormonal deficiencies.
  • Diversion:
  • Ammonia detoxification in urea cycle defects via benzoate.
  • Inhibition:
  • Use of statins to inhibit cholesterol synthesis in hypercholesterolemia.
• Depletion:
  • Removal of harmful metabolites through therapeutic interventions.