Genetic Disorders

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Genetic Disorders
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• Single-Gene Disorders with Nonclassic Inheritance
  
• do not follow classic Mendelian principles
• Four categories
• Triplet-repeat mutations
• gonadal mosaicism
• genomic imprinting
• mutations in mitochondrial genes

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• Single-Gene Disorders with Nonclassic Inheritance
  
• 1. Triplet-repeat mutations
• Mutation is characterized by a long repeating
  sequence of three nucleotides
• FRAGILE-X SYNDROME
• Fragile X discontinuity of staining or as a
  constriction in the long arm of the X chromosome
  (cultured in a folate-deficient medium)
• affected sequences share the nucleotides guanine
  (G) and cytosine (C)
• 2nd most common genetic cause of mental
  retardation (1st - Down syndrome)
• Affected males - mentally retarded (IQ-20 to 60)
• Physical phenotype
• Long face with a large mandible
• Large everted ears
• Large testicles (Macro-orchidism- 90 of
  postpubertal males )
• Hyper extensible joints
• High arched palate, and mitral valve prolapse

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• Single-Gene Disorders with Nonclassic Inheritance
  
• Fragile-X Syndrome
• Carrier males
• 20 of males-carry a fragile X mutation are
  clinically and cytogenetically normal
• Have affected grandchildren
• Transmitting males.
• Affected females- 50 of carrier females are
  affected (i.e., mentally retarded)
• Risk of phenotypic effects
• Sherman paradox
• brothers of transmitting males - 9 risk of
  having mental retardation
• Grandsons of transmitting males - 40 risk
• Anticipation- clinical features worsen with each
  successive generation
• Mutation in Xq27.3 (FMR-1 gene)
• Multiple tandem repeats of the nucleotide
  sequence CGG in its 5' untranslated region
• During the process of oogenesis, ( not
  spermatogenesis), premutations can be converted
  to mutations by triplet-repeat amplification.
• Abnormal methylation -resulting in
  transcriptional suppression of FMR-1

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Chromosome is "broken or fragile site
Broken or Fragile site
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FRAGILE-X SYNDROME
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• Single-Gene Disorders with Nonclassic Inheritance
  
• Fragile-X Syndrome
• loss of function of the familial mental
  retardation protein (FMRP).
• most abundant in the brain and testis (most
  affected in this disease)
• absence of such F MRP-mediated regulation ?
  interferes with synaptic transmission ? causes
  mental retardation
• Diagnosis
• PCR-based diagnosis - method of choice for
  diagnosis
• Southern blot analysis is for
• genetic counseling
• prenatal postnatal distinction between
  premutations and mutations
• Other Diseases Nucleotide Repeats
• Huntington disease they occur during
  spermatogenesis
• fragile-X syndrome, expansions occur during
  oogenesis

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Loss of function of the familial mental
retardation protein (FMRP)
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Table 5-9. Summary of Trinucleotide Repeat
Disorders
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Table 5-9. Summary of Trinucleotides Repeat
Disorders
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Table 5-9. Summary of Trinucleotide Repeat
Disorders
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• 2. Germ line or gonadal mosaicism
• Some patients do not have affected parents
• Disorder results from a new mutation in the egg
  or the sperm
• Their siblings are neither affected nor at
  increased risk
• Violates the laws of mendelian inheritance
• Mutation that occurs postzygotically during early
  (embryonic) development
• Gonadal mosaicism may be responsible for such
  unusual pedigrees

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• 3. Genomic imprinting
• Homologous maternal and paternal chromosomes
• Epigenetic process Imprinting
• Imprinting (silencing)
• Maternal Paternal
• Imprinting (silencing)
• occurs in the ovum or the sperm, before
  fertilization stably transmitted to all somatic
  cells through mitosis
• Two uncommon genetic disorders
• Prader -Willi syndrome
• Angelman syndrome.

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• 3. Genomic imprinting
• Prader -Willi Syndrome
• Characterized by
• Mental retardation, short stature, hypotonia,
  obesity, small hands and feet, and hypogonadism
• Molecular basis
• Most of cases (65 to 70) - del(15)
• The paternally derived chromosome 15 involved in
  all cases
• Biochemical basis
• Methylation of DNA is known to affect gene
  expression
• Histone H4 deacetylation methylation

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• 3. Genomic imprinting
• Angelman Syndrome
• Characterized by
• also mentally retarded
• ataxic gait, seizures, and inappropriate laughter
  ("happy puppets.)
• Molecular basis
• Deletion of this maternal gene on chromosome 15
• uniparental disomy of paternal chromosome 15.
• Biochemical basis
• affected gene is a ubiquitin protein- ligase ( it
  has role in the ubiquitin - proteasome
  proteolytic pathway)
• 10 of cases -due to a point mutation in the
  maternal allele
• Parent-of-origin effects
• Huntington disease and Myotonic dystrophy
• Tumor genesis

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Mutations in mitochondrial genesleber hereditary
optic neuropathy
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• 4. Mitochondrial diseases
• unique Feature - maternal inheritance
• Mothers transmit mtDNA ?to both male and female
  offsprings
• Daughters but not sons transmit the DNA further
  to their progeny
• Characterized by
• Human mtDNA contains 37 genes
• 24 are needed for mtDNA translation
• 13 encode subunits of the respiratory chain
  enzymes (oxidative phosphorylation)
• Organs most dependent on oxidative
  phosphorylation
• CNS, skeletal muscle, cardiac muscle, liver, and
  kidneys
• Tissues-harbor both wild-type and mutant mtDNA-
  Heteroplasmy
• Minimum number of mutant mtDNA must be present to
  cause oxidative dysfunction - Threshold effect
• Leber hereditary optic neuropathy -prototype
• Neurodegenerative disease
• Progressive bilateral loss of central vision
• First noted between ages 15 and 35,
• Cardiac conduction defects
• Minor neurologic manifestations