Genetic Disorders

• FIRST SEMESTER: GENERAL PATHOLOGY
• GENETIC DISORDERS: MENDELIAN DISORDERS
• Jose Franco O. Villaroya, MD, DPSP, APCP
• O U T L I N E
• Genetics


  Central dogma: Gene expression - DNA to RNA to Protein
• DNA Organization


  • Base pairs of purine and pyrimidine
  • DNA loops twice around a histone
  • Nucleosomes coiled into chromatin fiber which are further condensed
• Gene


  • Basic unit of heredity
  • Sequence of nucleotides in the DNA
  • Section of DNA within genome that carries the information to make a molecule
  • Exons - contain actual genetic information
  • Introns - intervening sequences; non-coding; function for regulation of gene expression
  • Alternative splicing produces variety of proteins from a single pre-mRNA
• Classification of Genetic Disorders

  • Disorders related to mutations in single genes with large effects (Mendelian disorders)
  • Chromosomal disorders
  • Complex multigenic disorders/multifactorial disorders
• Mutation


  • Permanent change in the DNA
  • Mutations that affect germ cells are transmitted to the progeny and can give rise to inherited diseases
  • Mutations that arise in somatic cells do not cause hereditary diseases but are important in the genesis of cancers and some congenital malformations
• Types of Point Mutations

  • Missense mutations
  • Nonsense mutations
• Mutations within noncoding sequences

  • Mutations in noncoding regions may interfere with binding of transcription factors
  • Results in reduction or absence of transcription
  • Effects: Defective splicing, Failure to generate mature DNA, Gene product is not synthesized
• Deletions and insertions


  • Mutations caused by indel (insertion/deletion) of bases in the DNA
  • Reading frame will remain intact if the number of base pairs involved is 3 or multiple of 3
  • Frameshift mutation if the number of affected coding bases is not multiple of 3
• Alterations in protein-coding genes other than mutations

  • Amplifications or deletions
  • Translocations
• Trinucleotide-repeat mutations


  • Characterized by amplification of a sequence of 3 nucleotides
  • Almost all affected sequences share the nucleotides guanine (G) and cytosine (C)
  • Dynamic (degree of amplification increases during gametogenesis)
  • Example: Fragile X syndrome
• Mendelian Disorders
• Types of Mendelian Disorders

  • Autosomal Dominant
  • Autosomal Recessive
  • X-linked disorders
• Autosomal Dominant Disorders


  • Manifested in the heterozygous state
  • Both males and females are affected, both can transmit the condition
  • 50% chance of offspring having the disease
  • Some proportion of patients do not have affected parents (new mutations)
  • Clinical features can be modified by variations in penetrance and expressivity
  • Incomplete penetrance - individuals inherit the mutant gene but are phenotypically normal
  • Expressivity - degree a phenotype is expressed by those having the mutant gene
• Loss-of-function mutation


  Most mutations lead to the reduced production of a gene product or give rise to a dysfunctional or inactive protein
• Gain-of-function mutations


  • Increase in normal function of protein
  • Change a function of a protein (new activity)
• Autosomal Recessive Disorders


  • Make up the largest category of Mendelian disorders
  • Both alleles at a given gene locus are mutated
  • Expression of the defect tends to be more uniform compared to AD disorders
  • Complete penetrance is common
  • Onset of disease occurs early in life
  • Many of mutated genes encode enzymes
• 1. Linked Disorders


  • All sex-linked disorders are X-linked, and almost all are recessive
  • Males (XY) are hemizygous to the X chromosome, thus X-linked recessive disorders are expressed in males
  • Affected male does not transmit the disorder to his sons, but all daughters are carriers
  • Heterozygous female usually does not express the full phenotypic change because of the paired normal allele
• Biochemical and Molecular Basis of Mendelian Disorders


  • Enzyme defects and their consequences
  • Defects in receptors and transport systems
  • Alterations in the structure, function, or quantity of non-enzyme protein
  • Genetically determined adverse reaction to drugs
• Figure 1. A possible metabolic pathway in which a substrate is converted to an end product
• Much more commonly, the normal allele is inactivated in only some of the cells, and thus a heterozygous female expresses the disorder partially
• In females with G6PD deficiency, a proportion of the red cells may be derived from precursors with inactivation of the normal allele
• Females are carriers of the trait and are susceptible to drug-induced hemolytic reactions
• Biochemical and Molecular Basis of Mendelian Disorders


  • Enzyme defects and their consequences
  • Defects in receptors and transport systems
  • Alterations in the structure, function, or quantity of non-enzyme protein
  • Genetically determined adverse reaction to drugs
• These were not thoroughly lectured. Details of each biochemical and molecular basis are lifted from the book
• Substrate


  The substance that an enzyme acts upon
• Enzyme 1, 2, 3


  Intracellular enzymes that convert the substrate into an end product through intermediates
• A minor pathway producing small quantities of M1 and M2 also exists
• Enzymes


  • They increase the rate of chemical reactions without themselves being consumed or permanently altered by the reaction
  • They increase reaction rates without altering the chemical equilibrium between reactants and products
• Receptor-mediated endocytosis


  The process by which biologically active substances are actively transported across the cell membrane
• Defects in receptors and transport systems

  • Familial hypercholesterolemia - reduced synthesis or function of LDL receptors
  • Cystic fibrosis - defective transport system for chloride and bicarbonate ions
• Alterations in the structure, function or quantity of non enzyme proteins

  • Sickle cell disease - defects in the structure of the globin molecule
  • Osteogenesis imperfecta - defect in collagen
  • Hereditary spherocytosis - defect in spectrin
  • Muscular dystrophies - defect in dystrophin
• Pharmacogenetics


  Genetically determined enzyme deficiencies that are unmasked only after exposure of the affected individual to certain drugs
• Genetically determined adverse reaction to drugs

  • G6PD deficiency - administration of anti-malarial drug, primaquine, resulting to severe hemolytic anemia
• Marfan syndrome is a disorder of connective tissues, manifested by skeletal, eyes and cardiovascular system
• Marfan syndrome


  Autosomal dominant inheritance (majority)
• Two homologous forms of fibrillin

  • Fibrillin-1 (FBN1 gene, chromosomes 15q21.1) - Marfan syndrome
  • Fibrillin-2 (FBN2 gene, chromosomes 5q23.31) - Congenital contractural arachnodactyly