Unit 3 Disease Pathogenesis

This unit will introduce candidates to the genetic processes involved in disease pathogenesis including molecular and cytogenetic pathogenic events leading to disease. Molecular pathogenesis focusing on mutation functional types and genotype/phenotype relationships including modifying factors. Cytogenetic pathogenic events will focus on aneuploidy and structural rearrangements. The unit will also provide examples of specific types of disorders including inborn errors of metabolism, triplet repeat disorders and cell function disorders, including disorders affecting signalling, protein trafficking, cell cycle and ion channel disorders.

Learning Outcomes

3.1 Describe the different types of chromosomal aberrations and give examples of diseases associated with each including:Describe the different types of chromosomal aberrations and give examples of diseases associated with each including:

  • Aneuploidy: Trisomy 13, 18, 21, Klinefelter syndrome and Turner syndrome.
  • Structural rearrangements: Balanced and unbalanced
  • Loss of heterozygosity
  • Imprinting

3.2 Understand how genotype affects phenotype. Candidates are expected to understand:Understand how genotype affects phenotype. Candidates are expected to understand:

  • How position of the mutation may affect phenotype e.g. domain or amino acid.
  • How the nature of the mutation may affect phenotype
    • Loss of function (LOF) mutations
      • Describe haploinsufficiency
      • Differentiate between truncating and non-truncating mutations
    • Gain of function (GOF) mutations (e.g. hypermorph, antimorph, neomorph)
  • How mutations outside of the coding region might affect expression
  • How a single gene can result in different phenotypes (pleitrophy). Be familiar with FBN1 as an example.
  • How the manifestation of some disorders requires mutations to occur in two (digenic or more (oligogenic) genes. Be familiar with Bardet-Biedl as an example.

3.3 Be familiar with the genotype/phenotype relationships for the following conditions:Be familiar with the genotype/phenotype relationships for the following conditions:

  • Osteogenesis Imperfecta
  • Haemaglobinopathies

3.4 Be familiar with trinucleotide repeats, the categorization of repeat ranges, the concept of anticipation and manner in which expansions can result in a LOF or GOF. Give examples of diseases caused by both LOF and GOF mutations.

3.5 Outline factors other than genotype which would modify phenotype.

3.6 Be familiar with the different classes/categories of metabolic disorders and a condition from each. Be aware of methods of diagnosing metabolic disorders and their strengths and limitations.

3.7 Be familiar with the categories of disorders which can arise due to cellular dysfunction including enzyme function, signalling pathways, cell structure/filaments, vesicle transport, cell-cell communication, protein trafficking, DNA repair, cell cycle, ion channels. Give examples of diseases from each category.

Resources

  • 3.1 Strachan and Read (2011) Human Molecular Genetics, Fourth Edition, Garland Science and Taylor and Francis Group, New York, USA
  • 3.2 Human Genetics and Genomics, 4th Edition Bruce Korf & Mira Irons 2012, Wiley-Blackwell
  • 3.3 GeneReviews
  • URL: http://www.ncbi.nlm.nih.gov/books/NBK1116/
  • 3.4 Essentials of Genetics by W.S. Klug, M.R. Cummings, C.A. Spencer and M.A. Palladino ISBN-10: 0134047796, 2015 by Pearson publications
  • 3.5 Olkkonen and Ikonen (2006) When intracellular logistics fails - genetic defects in membrane trafficking Journal of Cell Science 2006 119: 5031-5045
  • 3.6 Valle, Beaudet, Vogelstein, Kinzler, Antonarakis, Ballabio, Gibson, Mitchell. The Online Metabolic and Molecular Bases of Inherited Disease
  • URL: http://ommbid.mhmedical.com/book.aspx?bookID=971