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Molecular basis of genetic disease

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Molecular basis of genetic disease

  1. 1. Molecular and cellular basis of genetic disorders.
  2. 2. OUTLINE: Patterns of inheritance O 1. Mendelian; • Autosomal Dominant • Autosomal Recessive • X-linked Recessive • X-linked Dominant • Y-linked O 2. Non mendelian; • Modifiers to monogenic inheritence. • Complex/Polygenic inheritence O 3. Chromosomal disorders.
  3. 3. Important terms. O Genes: Segments of the DNA on chromosomes that code for a specific protein. O Allele; The different forms of the same gene found on the different chromosomes. O Homozygous Vs Heterozygous. O Genotype Vs Phenotype.
  4. 4. Mendelian 1. First discovered and postulated by Gregor Mendel. 2. Monogenic 3. Classic type with predictable inherittence patterns; punnet squares, pedigree charts.
  5. 5. Autosomal Dorminance O Single mutation on one copy of a gene. O Autosomes involved. O Affected individuals are heterozygous for a disease mutation. O Males & females affected equally. O Does not skip generations O 50 percent risk that an affected parent will pass a mutated allele to the child.) O As a rule; carriers don’t exist!! O Mostly affects structural and regulator/membrane proteins.
  6. 6. Autosomal Recessive O Mutation on both alleles. O Autosomes involved. O Compound heterozygous mutations (two different mutations affecting the same gene) O Or one homozygous mutation (the same mutation on both alleles of a gene). O Both males and females are equally affected. O Carriers of autosomal recessive mutations have one allele with a mutation and one normal allele, and are usually unaffected. O 25 percent of the couple's children will be affected, and 75 percent will be unaffected. Two-thirds of unaffected offspring will be heterozygous carriers and one-third homozygous. O Usually affect enzyme proteins.
  7. 7. X-linked O X or Y chromosome. O X-linked recessive inheritance is most common. O More prevalent in males. O Females, however, would only manifest the phenotype if they were homozygous for the gene (which would only occur in the rare event that both the father and mother are carriers) O e.g X-linked recessive diseases are Hemophilia VIII and IX. O X-linked dominant traits occur in both sexes. O More severe among males due to the absence of a normal X chromosome O F:M= 2:1 O Y-linked; Males only. sexual dysfunction; no other confirmed examples of other types of Y-linked diseases.
  8. 8. Variations; 1. Penetrance; phenotypic expression of mutation. O Incomplete penetrance skips variation e.g O Variable expressivity e.g NF Type 1. 2. Age (adult onset conditions) O Huntington’s symptoms typically become worse as one ages. O MEN1, 7% at age 10, 100% at 60yrs
  9. 9. 5. New mutations skip generations. 6. Sex limited/influenced mutations; eg male pattern boldness. *How do you tell this apart from X- linked recessive? 7. Pleiotropy e.g SCD 8. Mosaicism;. E,g Turner’s syndrome, Down’s syndrome 9. Anticipation; eg Myotonic dystrophy, Huntington’s.
  10. 10. 9. Codominance; ABO blood grouping 10. Incomplete dorminance eg in SCD 11. Heterogeneity e.g in DM type 1 12. Environmental modification. E.g in PKU with dietary modification, Emphysema and smoking regulation. 13. Imprinting. E.g PWS (paternal) and Angelman Syndrome (maternal)
  11. 11. Enzyme disorders O Accumulation of tissue damaging substrate e.g lack of phenyl hydroxylase= no breakdown of phenyl alanine= PKU O Metabolic block and deficiency of end product e.g lack of tyrosinase= no melanin= albinism O Failure to inactivate tissue-damaging substrate e.g alpha1 antitrypsin deficiency(protease)= unchecked pulmonary neutrophil activity= destruction of alveolar elastin= emphysema O Genetically determined adverse reactions to drugs e.g G-6PD deff.
  12. 12. Receptor and transport protein disorders O Familial hypercholesterolemia; deficient LDL receptor O Hemoglobinopathies SCD Thalasemias Osteogenesis imperfecta
  13. 13. Non classic monogenic inheritence O Trinucleotide repeat mutations; Expansion of trinucleotides sharing G&C, unstable DNA Might exist in coding or non coding regions Parental origin predisposes to varying types of expansion Most neurogenic disorders; Fragile X syndrome, Huntington’s O Genomic imprinting; e.g Prader Willi Syndrome and Angelman syndrome.
  14. 14. ……continued O Mitochondrial Inheritance; • Purely maternal origin. • Affects both males and females but females transmit • mtDNA encodes enzymes involved in oxidative phosphorylation • Affects organs most dependent above metabolism; CNS, Skeletal & cardiac muscle, Kidneys. • e.g Leber hereditary optic neuropathy. O Gonadal mosaicism; • Mutations in early embryonic dev’t • Affects cells destined to form gonads, somatic cells normal • Phenotypically normal parent, affected offspring.
  15. 15. Complex/Polygenic disease/Non- mendelian O Polygenic involvement with continuous phenotypic variations in affected populations. O Normal phenotypic characteristics under this; skin color, height, intelligence, curling of hair. O Often modified(amplified) by environmental factors O Classic example; DM O Incomplete penetrance and variable expressivity of monogenic trait can overlap so in essence diseases in this category are classified by elimination
  16. 16. Chromosomal disorders.
  17. 17. Karyotyping…. O Cytogenetic method. O Normally diploidy with 22 homologous autosomal pairs and 1 sex chromosome pair= 46XX/46XY. O Mitotic Inhibitor(N-diacetyl-N-methylcolchicine) applied to cell in metaphase. O Stained by Giemsa(G-banding) O Pairs arranged according to length followed by sex chromosome. O Shorthand; 47,XY, +21; Xp21.2
  18. 18. Polyploidy O Addition of complete haploid sets of DNA O 2n + n =3n (triploidy), tetratploidy. O Occur at fertilization or cleavage errors during mitosis O Incompatible with life and often lead to abortions or IUFD
  19. 19. Aneuploidy 1. Non disjunction; O Gametogenesis O n+1 or n-1 O Offspring; Trisomy(2n+1) and Monosomy(2n-1) 2. Anaphase Lag; O Whole Xsome in meiosis or chromatid in mitosis left out O Normal cell + monosomic cell.
  20. 20. O When x-linked; compatible with life O When autosomal usually= intrauterine demise. O E.g Edward’s 47, XX+18 47, XY+18 Down’s 47,XX+21 or 47,XY+21 Turner 45,X
  21. 21. Balanced structural Inversion; O Paracentric and pericentric. O Phenotypically normal
  22. 22. Translocation
  23. 23. Types of translocation.. O Reciprocal; 46,XX,t(2;5)(q13;p14) O Insertions O Robertsonian; e.g Down’s, Edward’s.
  24. 24. Unbalanced structural Deletions O Chromosomal tearing or unequal cross-over. O Terminal or interstitial. O 46, XY, del(16)(p11.2p13.1) O Ring deletion; 46,XY,r(14) O Di-George, Velocardiofacial syndromes and schizophrenia
  25. 25. Duplication O Unequal cross over or abnormal segregation.
  26. 26. Isochrome….. O Deletion-duplication mutation. O Centromere cleavage; joining of short arms and long arms
  27. 27. Sex chromosomal disorders
  28. 28. Referrences Up-to-date; O Benjamin A Raby, MD, MPHSection Editor:Anne Slavotinek, MBBS, PhDDeputy Editor:Jennifer S Tirnauer, MD Basic principles of genetic disease O Benjamin A Raby, MD, MPHSection Editor:Anne Slavotinek, MBBS, PhDDeputy Editor:Jennifer S Tirnauer, MD Non-Mendelian inheritance patterns of monogenic diseases .

Editor's Notes

  • 7. Pleiotropy is the term used to describe a constellation of varying clinical effects, usually in different organ systems, which can arise due to mutations in a single gene
    8. some cells carrying the mutation, while others do not
    9. severity of some diseases increases as the disease is passed on through generations
  • 9. Equal expressivity of dorminant alleles in offspring.
    Shared expressivity in offspring.
    several genes code for a single mutation
    is the differential expression of genetic material depending on whether it was inherited from the male(paternally imprinted=silenced =only maternal genes expressed) or female (vice versa)parent
  • MtDNA has 37 genes, 22 transcribed into tRNA, 2 into Rrna, the rest encode subunits of respiratory chain enzymes.
    Threshold effect