GENETIC DISORDERS (Mutations & Mendelian Disorders) <ul><li>Dr. Shahab Riaz </li></ul>
Generalized Classification of Human Diseases <ul><li>Environmentally Determined </li></ul><ul><li>Genetically Determined <...
<ul><li>Hereditary Disorder: </li></ul><ul><li>The disorder derived from one’s parents. </li></ul><ul><li>Familial Disorde...
MUTATIONS <ul><li>Permanent change in the DNA or Genome. </li></ul><ul><li>Germ cell mutations    progeny    inherited d...
Mutation Classification <ul><li>Genome Mutations: </li></ul><ul><li>Loss or gain of whole chromosomes    monosomy or tris...
Genome Mutation
Genome Mutation
Chromosome Mutation
Gene Mutations Classification <ul><li>Point Mutation (Single Base Substitution): </li></ul><ul><li>A single nucleotide bas...
Point Mutation
Frameshift Mutation
Trinucleotide Repeat Mutations <ul><li>Special category of mutations </li></ul><ul><li>Amplification of a sequence of thre...
 
Point Mutations Classification <ul><li>Transitions :   </li></ul><ul><li>(more common)   replacement of a  purine  base wi...
General Principles of Effects of Gene Mutations <ul><li>Point Mutations within Coding Sequences (Exons): </li></ul><ul><li...
For example,  sickle-cell disease  is caused by a single point mutation (a missense mutation) in the beta- hemoglobin   ge...
General Principles of Effects of Gene Mutations <ul><li>Mutations within Non-coding Sequences (Introns): </li></ul><ul><li...
General Principles of Effects of Gene Mutations <ul><li>Deletions & Insertions: </li></ul><ul><li>Small deletions or inser...
(Paradox) Protection by Mutations <ul><li>Uncommonly the mutations may be protective </li></ul><ul><li>e.g., </li></ul><ul...
Mendelian Disorders <ul><li>All Mendelian disorders    result of expressed mutations in single genes of large effect </li...
Mendelian Disorders <ul><li>Some autosomal mutations    partial effect in heterozygotes    full expression in homozygote...
Mendelian Disorders <ul><li>Pleiotropism: </li></ul><ul><li>when a single mutant gene leads to many end-effects </li></ul>...
Transmission Patterns of Single Gene Disorders <ul><li>Autosomal Dominant </li></ul><ul><li>Autosomal Recessive </li></ul>...
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Genetic disorders 2

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Genetic Disorders (No 2)

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Genetic disorders 2

  1. 2. GENETIC DISORDERS (Mutations & Mendelian Disorders) <ul><li>Dr. Shahab Riaz </li></ul>
  2. 3. Generalized Classification of Human Diseases <ul><li>Environmentally Determined </li></ul><ul><li>Genetically Determined </li></ul><ul><li>Both Environmental and Genetic factors </li></ul>
  3. 4. <ul><li>Hereditary Disorder: </li></ul><ul><li>The disorder derived from one’s parents. </li></ul><ul><li>Familial Disorder: </li></ul><ul><li>The hereditary disorder transmitted in the germ line through the generations. </li></ul><ul><li>Congenital Disorder: </li></ul><ul><li>Simply implies “Born With”. Some congenital diseases are not genetic e.g., congenital syphilis. </li></ul><ul><li>Similarly not all genetic diseases are congenital e.g., Huntington’s Disease  age 20s-30s </li></ul>
  4. 5. MUTATIONS <ul><li>Permanent change in the DNA or Genome. </li></ul><ul><li>Germ cell mutations  progeny  inherited diseases </li></ul><ul><li>Somatic cell mutations don’t cause hereditary diseases but  some cancers / congenital malformations </li></ul>
  5. 6. Mutation Classification <ul><li>Genome Mutations: </li></ul><ul><li>Loss or gain of whole chromosomes  monosomy or trisomy </li></ul><ul><li>Chromosome Mutations: </li></ul><ul><li>Rearrangement of genetic material  visible structural changes in chromosome </li></ul><ul><li>1 and 2 transmitted infrequently bcz most incompatible with life </li></ul><ul><li>Gene Mutation: </li></ul><ul><li>- Most of the mutations associated with hereditary diseases </li></ul><ul><li>- Partial or complete deletion of a gene </li></ul><ul><li>- OR more often a single base is affected </li></ul>
  6. 7. Genome Mutation
  7. 8. Genome Mutation
  8. 9. Chromosome Mutation
  9. 10. Gene Mutations Classification <ul><li>Point Mutation (Single Base Substitution): </li></ul><ul><li>A single nucleotide base is substituted by a different base </li></ul><ul><li>Frameshift Mutation (Framing Error): </li></ul><ul><li>(Less common) caused by “ indels” one or two base pairs may be inserted into or deleted from the DNA  alterations in the reading frame of the DNA strand bcz triplet nature of coding codons </li></ul><ul><li>- number of nucleotides  is not evenly divisible by three from a  DNA  sequence </li></ul><ul><li>- completely different translation from the original </li></ul><ul><li>c. Trinucleotide Repeat Mutations: </li></ul>
  10. 11. Point Mutation
  11. 12. Frameshift Mutation
  12. 13. Trinucleotide Repeat Mutations <ul><li>Special category of mutations </li></ul><ul><li>Amplification of a sequence of three nucleotides </li></ul><ul><li>Although the specific nucleotide sequence differs in various disorders but most have “C” and “G”. </li></ul><ul><li>E.g., Fragile-X syndrome (prototypic of this category)  250-4000 tandem repeats of sequence CGG within a gene called FMR-1 </li></ul><ul><li>In normal populations  small number  average 29 repeats </li></ul><ul><li>Abnormal expression of FMR-1 gene  mental retardation </li></ul><ul><li>Dynamic feature of TRMs  amplification during gametogenesis </li></ul>
  13. 15. Point Mutations Classification <ul><li>Transitions : </li></ul><ul><li>(more common) replacement of a  purine  base with another purine or replacement of a  pyrimidine  with another pyrimidine </li></ul><ul><li>Transversions : </li></ul><ul><li>replacement of a purine with a pyrimidine or vice versa. </li></ul>
  14. 16. General Principles of Effects of Gene Mutations <ul><li>Point Mutations within Coding Sequences (Exons): </li></ul><ul><li>Code altered in triplet bases by single base substitution </li></ul><ul><li>If this mutation alters the meaning of genetic code and codes for a different amino acid  Mis-sense Mutations </li></ul><ul><li>If substituted amino acid causes little change in protein function  “Conservative” Mis-sense Mutation </li></ul><ul><li>If normal amino acid replaced by a very different one  </li></ul><ul><li>“ Non-conservative” Mis-sense Mutation </li></ul><ul><li>If point mutation changes an amino acid codon to a chain termination or Stop Codon  Non-sense Mutations </li></ul><ul><li>If codes for different amino acid but no functional protein change  Silent Mutations </li></ul>
  15. 17. For example,  sickle-cell disease  is caused by a single point mutation (a missense mutation) in the beta- hemoglobin   gene  that converts a GAG codon  into GTG, which encodes the  amino acid   valine  rather than  glutamic acid .
  16. 18. General Principles of Effects of Gene Mutations <ul><li>Mutations within Non-coding Sequences (Introns): </li></ul><ul><li>Deleterious effects may also result even if exons not involved </li></ul><ul><li>Most often without consequences, although there are exceptions </li></ul><ul><li>Promoter & Enhancer sequences  upstream or downstream of gene </li></ul><ul><li>If point mutations or deletions  regulatory sequences  interfere with binding of transcription factors  marked reduction or total lack of transcription </li></ul><ul><li>If the mutation occurs in the splicing seat of an intron  interfere with correct splicing of the transcribed  pre-mRNA  failure to form mature mRNA  no translation  no gene product synthesis </li></ul>
  17. 19. General Principles of Effects of Gene Mutations <ul><li>Deletions & Insertions: </li></ul><ul><li>Small deletions or insertions involving coding sequence  alterations in reading frame of DNA strand  Frame Shift Mutations </li></ul><ul><li>If base pairs are three or multiple of three  no frame shift </li></ul><ul><li>Instead an abnormal protein missing one or more amino acids is synthesized </li></ul>
  18. 20. (Paradox) Protection by Mutations <ul><li>Uncommonly the mutations may be protective </li></ul><ul><li>e.g., </li></ul><ul><li>HIV uses chemokine receptor CCR5 to enter cells  deletion in CCR5 gene  protection from HIV infection </li></ul>
  19. 21. Mendelian Disorders <ul><li>All Mendelian disorders  result of expressed mutations in single genes of large effect </li></ul><ul><li>Neither multifactorial inheritance nor chromosomal disorders </li></ul><ul><li>Every individual  5-8 deleterious genes  most recessive  no phenotypic effect </li></ul><ul><li>80-85% of these mutations are familial  remainder new mutations acquired de novo by affected individual </li></ul>
  20. 22. Mendelian Disorders <ul><li>Some autosomal mutations  partial effect in heterozygotes  full expression in homozygotes </li></ul><ul><li>Sickle cell anemia  HbA replaced by HbS  Homozygotes all Hb of HbS type (full blown sickle cell anemia) </li></ul><ul><li>Heterozygotes  partial HbS , partial HbA  sickling and anemia in O2 tension (Sickle Cell trait) </li></ul><ul><li>Aside from Dominant and Recessive  “Codominance”  both alleles of a gene pair fully expressed in a heterozygote  e.g., blood group antigens </li></ul>
  21. 23. Mendelian Disorders <ul><li>Pleiotropism: </li></ul><ul><li>when a single mutant gene leads to many end-effects </li></ul><ul><li>e.g., sickle cell  HbS , sickling, hemolysis, logjam in small vessels, splenic fibrosis, organ infarcts, bone changes </li></ul><ul><li>Genetic Heterogeneity: </li></ul><ul><li>when mutations at several genetic loci produce the same effect or trait </li></ul><ul><li>e.g., profound childhood deafness  any of 16 different types of autosomal recessive mutations </li></ul><ul><li>Polymorphism: </li></ul><ul><li>not all nucleotide changes produce genes that cause disease  when such DNA change occurs in at least 1% of population called Polymorphism </li></ul>
  22. 24. Transmission Patterns of Single Gene Disorders <ul><li>Autosomal Dominant </li></ul><ul><li>Autosomal Recessive </li></ul><ul><li>X-linked </li></ul>
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