In-Depth Notes on Genetic Diseases

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

Mutations in Different Classes of Proteins

Organelles

• Mitochondria

  • Oxidative Phosphorylation:
  • ND1 protein of electron transport chain linked to Leber Hereditary Optic Neuropathy.
  • Translation of Mitochondrial Proteins:
  • tRNA leu related to MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes).
  • 12S RNA linked to sensorineural deafness.

• Peroxisomes

  • Biogenesis:
  • 12 proteins implicated in Zellweger Syndrome.

• Lysosomes

  • Lysosomal Enzymes:
  • Hexosaminidase A deficiency causes Tay-Sachs Disease.
  • α-L-iduronidase deficiency linked to Hurler Syndrome.

Extracellular Proteins

• Transport

  • β-Globin mutations lead to Sickle Cell Disease and β-Thalassemia.

• Morphogens

  • Sonic hedgehog mutations connected to Holoprosencephaly.

• Protease Inhibition

  • α₁-Antitrypsin deficiency results in emphysema and liver disease.

• Hemostasis

  • Deficiency in Factor VIII results in Hemophilia A.

• Hormones

  • Insulin mutations lead to rare forms of Type 2 Diabetes Mellitus.

• Extracellular Matrix

  • Collagen type 1 abnormalities associated with Osteogenesis Imperfecta.

• Inflammation/ Infection Response

  • Complement Factor H mutations can cause Age-related Macular Degeneration.

Cytoplasm

• Metabolic Enzymes

  • Phenylalanine Hydroxylase: Mutations cause Phenylketonuria (PKU).
  • Adenosine Deaminase: Linked to Severe Combined Immunodeficiency.

• Cytoskeleton

  • Dystrophin mutations lead to Duchenne Muscular Dystrophy.

Nucleus

• Developmental Transcription Factors

  • Pax6 mutations cause Aniridia.

• Genome Integrity

  • BRCA1, BRCA2 mutations increase risk for Breast Cancer.
  • Defects in DNA mismatch repair proteins associated with Hereditary Nonpolyposis Colon Cancer.

• RNA Translation Regulation

  • FMRP, an RNA binding protein, implicated in Fragile X Syndrome.

• Chromatin-associated Proteins

  • MeCP2 mutations cause Rett Syndrome.

• Tumor Suppressors

  • Rb protein mutations linked to Retinoblastoma.

• Oncogenes

  • BCR-Abl oncogene linked to Chronic Myelogenous Leukemia.

Cell Surface

• Hormone Receptors

  • Androgen Receptor mutations cause Androgen Insensitivity.

• Growth Factor Receptors

  • FGFR3 mutations lead to Achondroplasia.

• Metabolic Receptors

  • LDL Receptor mutations cause Hypercholesterolemia.

• Ion Transport

  • CFTR mutations linked to Cystic Fibrosis.

• Antigen Presentation

  • HLA loci, specifically DQB1, linked to Type 1 Diabetes Mellitus.

Expression of Genes

• Housekeeping Genes: Ubiquitous expression; essential for basic cellular function.
• Specialty Genes: Tissue-specific expression, defining unique functions in specific tissues.
  • Average cell expresses approximately 10,000 genes.

Gene Expression and Disease Specificity

• Tissue-specific gene mutations generally affect that tissue; exceptions exist (e.g., PKU).
• Some diseases arise from mutations in housekeeping genes affecting multiple tissues; e.g., Tay-Sachs disease - HEXA gene expressed in many tissues but primarily affects neurons.

Diseases Related to Enzymes and Receptors

Enzymes

• Phenylalanine Hydroxylase (PAH):

  • Mutation leads to PKU, characterized by the accumulation of Phenylalanine causing brain damage.
  • Treatment involves dietary restriction of phenylalanine-rich foods (meat, eggs, dairy).

• Variant PKU:

  • Full PKU shows 1% PAH activity while variant PKU exhibits >1% PAH activity, resulting in less severe symptoms.
  • Over 700 different mutations present, leading to clinical heterogeneity.

Disorders Related to Receptor Proteins

• Familial Hypercholesterolemia:
  • Increased lipids in the blood linked to mutations in the LDL receptor gene (LDLR).
  • Mutations in LDLR result in varying severity based on inheritance; homozygotes typically exhibit severe forms.

CFTR Gene and Cystic Fibrosis

• Cystic Fibrosis affects 1 in 2,500 live births.
  • CFTR gene encodes for Cl- channel, primarily involving alteration of mucosal surface hydration.
  • Most common mutation is ΔF508, particularly prevalent in the white population, occurring in approximately 70% of cases.
• Pleiotropic effects exist; one gene mutation can affect multiple tissues leading to various symptoms, including poor lung function and male infertility.

CF Treatment

• Treatments include antibiotics, vitamin supplements for malabsorption, and innovative drugs like Trikafta which target specific alleles.

Duchenne Muscular Dystrophy (DMD)

• DMD is caused by mutations in the dystrophin gene, encoding a protein essential for muscle integrity.
  • X-linked recessive inheritance pattern affecting primarily males with symptoms such as muscle weakness, often debilitating by age 3, with complications leading to early mortality.
• High mutation frequency in dystrophin gene; 60% of patients have deletion alleles affecting muscle function.