Gene Defects

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Gene Defects

  1. 1. Gene defect/ chromosome mutations
  2. 2. Essential terms <ul><li>Mutation </li></ul><ul><li>Variation </li></ul><ul><li>Aneuploidy </li></ul><ul><li>Euploidy </li></ul><ul><li>Poluploidy </li></ul><ul><li>Monosomy </li></ul><ul><li>Trisomy </li></ul><ul><li>Non disjunction </li></ul><ul><li>Sex linked </li></ul><ul><li>Autosomal D/R </li></ul><ul><li>Monogenic </li></ul><ul><li>Polygenic </li></ul>
  3. 3. <ul><li>Any form of modification = </li></ul><ul><li>chromosomal mutation/aberration . </li></ul>
  4. 5. <ul><li>A Change in a Single DNA Base Can Cause a Mutation </li></ul>
  5. 6. Eg. Sickle cell anaemia <ul><ul><li>A mutation caused a GAG codon to change into a GUG codon in the gene for one of the protein chains of hemoglobin </li></ul></ul><ul><ul><li>mutation replaced the glutamic acid a2 with valine </li></ul></ul><ul><ul><li>Conseqences = hemoglobin stick together and causes damage to RBC = anemia </li></ul></ul><ul><ul><li>The mutation also gives some resistance to malaria in individuals with one sickle gene and one normal gene </li></ul></ul>
  6. 7. Inborn errors of metabolism <ul><li>Most mutations are harmful </li></ul><ul><li>Caused by chemical and physical agents which damage DNA (UV light, x-rays, many carcinogenic & mutagenic chemicals) </li></ul><ul><li>Approx. 600 genetic diseases known </li></ul><ul><li>Gene therapy = correcting defective gene </li></ul>
  7. 8. Autosomal recessive <ul><li>PKU = lacks the ability to synthesize an enzyme to convert the amino acid phenylalanine into tyrosine </li></ul><ul><li>Built up phenylalanine and abnormal breakdown products in the urine and blood. </li></ul><ul><li>Affects the CNS = mental impairment. </li></ul><ul><li>1 in 15,000 infants suffers from this problem. </li></ul><ul><li>PKU sufferers are placed on a diet low in phenylalanine sufficient for metabolic needs </li></ul>
  8. 9. Autosomal recessive <ul><li>Tay-Sachs Disease = degeneration of the nervous system. </li></ul><ul><li>Lack the ability to make the enzyme N-acetyl-hexosaminidase, which breaks down the ganglioside lipid. This lipid accumulates in lysosomes, casuing death to brain cells. </li></ul><ul><li>Symptoms manifest after birth. </li></ul><ul><li>Rarely survive past five years of age. </li></ul><ul><li>1 in 300,000 births) in general pop, but 1 in 3600 births among Jews </li></ul><ul><li>One in 28 American Jews is thought to be a carrier </li></ul>
  9. 10. Autosomal recessive <ul><li>Albenism = the lack of pigmentation in skin, hair, and eyes </li></ul><ul><li>1) the lack of enzyme along the melanin-producing pathway; </li></ul><ul><li>or 2) the inability of the enzyme to enter the pigment cells and convert the amino acid tyrosine into melanin. </li></ul>
  10. 11. Autosomal dominant <ul><li>Huntington’s disease - progressive destruction of brain cells. </li></ul><ul><li>The disease usually does not manifest until after age 20-30. </li></ul><ul><li>Polydactly is the presence of a sixth digit common with this trait. </li></ul>
  11. 12. Sex linked <ul><li>Red-green colorblindness. 8% M, 0.04% F. X. </li></ul><ul><li>Hemophilia- defective blood clotting protein </li></ul><ul><li>Muscular dystrophy- DMD. 1 in 35,000. Muscle wasting disease. </li></ul>
  12. 13. Variation in number <ul><li>Random error during the prod. of gametes. </li></ul><ul><li>Non disjunction= disruption of the normal distribution of chr to gametes. </li></ul><ul><li>Consequent of this failure of separation = variety of autosomal aneploid conds. Eg 47XXY, 45X </li></ul>
  13. 14. Sex determination <ul><li>XX , XY </li></ul><ul><li>Hormones affect phenotypic expression </li></ul><ul><li>All individuals have genes to develop into either sex. Depends on sex chromosome and meiosis. </li></ul><ul><li>Meiosis = creates genetic variability and ensures genetic consistency. Depends on fertilization. </li></ul>
  14. 15. Y chromosome <ul><li>Fewer genes. </li></ul><ul><li>PAR (pseudoautosomal regions) </li></ul><ul><li>MSY (male specific region of Y) </li></ul><ul><li>SRY (sex determining region of Y) sex determination </li></ul><ul><li>SRY encodes a gene product that triggers the gonadal tissue to form testes. Product = TDF </li></ul><ul><li>SRY present = testes and testosterone forms </li></ul><ul><li>SRY absent= gonads develop as ovaries </li></ul>
  15. 16. Susceptible genes <ul><li>contribute risk, but don’t cause it. </li></ul><ul><li>influence the age of onset, rate of progression, or help to protect against it </li></ul><ul><li>Different alleles may be associated with different degrees of susceptibility, or risk. </li></ul><ul><li>The APOE gene on chromosome 19 </li></ul><ul><li>An individual who has two copies of one variant allele of APOE is more likely to develop Alzheimer disease at an earlier age than an individual with a different APOE genotype. </li></ul>
  16. 17. Variation in chromosome number <ul><li>Aneuploidy = gain or loss one or more chr. </li></ul><ul><li>Monosomy = 2n – 1. eg. 45X </li></ul><ul><li>Trisomy = 2n + 1. </li></ul><ul><li>Euploidy = complete haploid set of chr (x) </li></ul><ul><li>Polypliody = more than 2 sets of chr. </li></ul><ul><li>Triploid = 3 sets </li></ul><ul><li>Tetraploid = 4 sets. </li></ul>
  17. 18. Klinefelter syndrome <ul><li>Aneuploidy = Extra X chromosome (XXY). </li></ul><ul><li>2 in 1000 male births. Lower incidence that 47XXY </li></ul><ul><li>Sex ? Intersexuality </li></ul><ul><li>Male genitalia and internal ducts but testes rudimentary and X produce sperm. </li></ul><ul><li>Tall, long arms/legs, large hands/ feet. </li></ul><ul><li>Gynecomastia and rounded hips. </li></ul><ul><li>Intelligence below normal range. </li></ul><ul><li>Y chromosome determines maleness. </li></ul>
  18. 19. Other abnormal karyotypes <ul><li>48 XXXY </li></ul><ul><li>48 XXYY </li></ul><ul><li>49XXXXY </li></ul><ul><li>49XXXYY </li></ul><ul><li>All are similar phenotypically to 47XXY. </li></ul><ul><li>The greater number of X chromomes, the greater the manifestations. </li></ul>
  19. 20. XXX karyotype <ul><li>47XXX. 1 in 1200 female. </li></ul><ul><li>Extra X chr appears to disrupt the balance of gen info needed for female developmt. </li></ul><ul><li>Some may be normal, others may have underdeveloped sex chrtc, sterility and mental impairment. </li></ul><ul><li>48XXXX </li></ul><ul><li>49XXXXX. </li></ul>
  20. 21. 47 XYY karyotype <ul><li>Additional Y chromosome. </li></ul><ul><li>Tall – over 6 feet. </li></ul><ul><li>In the past -Incarcerated – predispositon to criminal acts, personality disorders and subnormal intelligence. </li></ul><ul><li>High numbers in mental institutions. </li></ul><ul><li>Now –studies shows there is little consistent correlation between extra Y chromosome and behaioral problem. </li></ul>
  21. 22. Monosomy <ul><li>Turner syndrome 45X. </li></ul><ul><li>1 in 2000 female births. </li></ul><ul><li>Female genitalia and internal ducts, ovaries rudimentary. </li></ul><ul><li>Short stature, broad chest, skin flaps back of the neck, underdeveloped breasts. </li></ul><ul><li>Sex ?. </li></ul>
  22. 24. Partial monosomy <ul><li>Segmental deletions cri-du-chat syndrome. </li></ul><ul><li>1 in 50,000 births </li></ul><ul><li>Loss of small part of chr 5 = 46-5p. </li></ul><ul><li>Anatomical malformations – GI and cardiac complications, often mentally challenged. </li></ul><ul><li>Abnormal glottis and larynx develop. = infant cry </li></ul><ul><li>Longer the deletion = greater the impact of physical, psychomoter and mental skills. </li></ul>
  23. 25. Trisomy <ul><li>1866 J. Landon Down = Down syndrome </li></ul><ul><li>Trisomy 21 (47 +21). ND of chr 21. </li></ul><ul><li>1 in 800 live births. </li></ul><ul><li>Extra chromosome maternal? > in ageing mum. </li></ul><ul><li>12- 14 cht. Physical, psychomoter and mental develop. Impairment. </li></ul><ul><li>Mongoloid appearance = flat face, round head, short, short, broad hands </li></ul><ul><li>Short life span </li></ul><ul><li>Prone to RTI, heart malformations, > leukemia, alzheimer </li></ul><ul><li>Early diagnosis – Amniocentesis and CVS. </li></ul>
  24. 26. Other trisomy <ul><li>Patau syndrome = Trisomy 13 </li></ul><ul><li>1 in 19,000 births. </li></ul><ul><li>Mentally challenged, partially deaf, clrft palate, congenital malformation of most organ system. </li></ul><ul><li>Average survival rate = 3 mths. </li></ul><ul><li>Edwards syndrome = Trisomy 18 </li></ul><ul><li>Infants smaller than average newborn. </li></ul><ul><li>Congenital malf, death within 4 mths. (Pneumo ) </li></ul>

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