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Genetic disorders 2


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Genetic Disorders (No 2)

Genetic Disorders (No 2)

Published in: Health & Medicine, Technology

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