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Sex linked inheritance

?. Sex linked inheritance. Dr. habil . Kőhidai László SU, Dept . Genetics , Cell- & Immunobiology 2017. Aut. Aut. Dom. Dom. Rec. Rec. F: M / 1: 1. F: M / 1: 1. X-. X-. F: M / < M. F: M / F >. !. X Chrs linked dominant inheritance General characteristics.

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Sex linked inheritance

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  1. ? Sex linked inheritance Dr. habil. Kőhidai László SU, Dept. Genetics, Cell- & Immunobiology 2017.

  2. Aut Aut Dom. Dom. Rec. Rec. F: M / 1:1 F: M / 1:1 X- X- F: M / < M F: M / F >

  3. ! X Chrs linked dominant inheritanceGeneral characteristics • Offspring of affected male (X’Y) and healthy female (XX): male - healthy (XY) female – affected in 100% (X’X) • Affected mother (X’X or X’X’): 50% of sons and daughters are hetero- or homozygotes for the dominant X allel • Diseases are expressed in more severe forms in affected males • Mela : 2x Female

  4. ! X Chrs linked recessive inheritanceGeneral characteristics • Expressed only in homozygote (X’X’) females (~ autosomal recessive) • Hemizygote male (X’Y) is similar to the homozygote females • Affected fathers (X’Y) dauther is heterozygote (X’X) „carrier” • The trait reappears in the grandsons of the affected fathers – „criss-cross” inheritance • Male >> Female

  5. X Chrs linked traits/diseases (frequency) /10.000 Color blindness (red-green) 800 Fragile X 5 Duchenne muscular dystrophy 3 Haemophilia A 2 Haemophilia B 0.3 X-linked ichtyosis 2 X-linked agammagglobulinaemia 0.1

  6. ! Amelogenesis imperfecta X – Dominant Synthesis of enamel (external layer of teeth) is affected Heterozygote female – columnar pattern (X’X) Homozygote female and hemizygote male – sever clinical forms

  7. ! Genesaffected: Pathologicalproteins of enamel AMELX Xp22.3-1 amelogenin AMELY Yp11 amelogenin ENAM 4q13.3 enamelin (5%) MMP20 11q22.3 zománc metalloproteinase KLK-4 g 19q13.4 kallikrein-relatedpeptidase 4 WDR72 15q21.3 WD repeat-containing protein 72 FAM83H 8q24.3 family with sequence similarity 83, member H TUFT1 1q21 tuftelin 4q21ameloblastin

  8. ! Incontinentia pigmenti(X-Dom.) • Vesiclesintheskin • Irregularmelanindeposits • and pigmentation • Alopecia • Dentaldysorders • Mentalretardation30% • Affected retina 30% • Lethalinhemizygotes • Majority of patients is female

  9. Xp21-22 Hypophosphataemia (Vitamin D resistantrickets) (X-Dom) PHEX gene PHEX = Phosphate-regulating neutral endopeptidase • - Slowgrowing • - Ricketsinchildhood • Se P decreased • Frequency: 1/20.000 - bone, dentin mineralization - phosphatereabsorption (kidney)

  10. PTN – phosphatonin ~ a – active ~ i – inactive NPT2 – Na/PO3 cotransporter Marc K Drezner, KidneyInternations

  11. Mechanism of bloodclotting

  12. Xq28 ! Hemophilia(X-Rec) Deficiency of blood clotting Hemophilia A Factor VIII. deficiency 45%inversion (F8A) insertion of LINE-1 sequence 6%antibodiesaredeveloped tofactor VIII 26 exons 9 kb 1 in 5,000 ffi

  13. Xq26.3-27.1 ! Hemophilia(X-Rec) Deficiency of blood clotting Hemophilia B Factor IX. deficiency (proteasepraecursor) 2% deletion Insertion (ALU sequence) Animalmodel: IrishSetter 8 exons 34 kb 1/20,000-30,000 Male

  14. Hemophilia

  15. Colorblindness(X-Rec) Cones of retina detect the 3 basiccolors Opsin 3D structure is changed All transretinal Feeling light

  16. Xq28 Opsingenes: BCP 7q31-35 RCP Xq28 GCP Xq28 GCP – RCP 96%-oshomology GCP – BCP 43%-os homology 6 exons

  17. RCP insufficiencyPROTANOPIA GCP insufficiency DEUTERANOPIA BCP insufficiencyTRITANOPIA

  18. Red-greencolorblindness MalesFemales Red-greencolorblindness

  19. Rett syndrome (1) • Developes only in females • Normal development lasts 6-18 months age • Loss of speach • Balance and coordination problems • Microcephaly, ataxia, autism transient hyperventillation • In the next phase the disease is more stable, and patients will reach adult age

  20. ! Rett syndrome (2) • Locusaffected Xp28 • MutationsingeneMeCP2 • The protein associatestotheCpGbases of the methylated DNA • Methylationinhibitstranscription of thegene • Methylationpattern is limited tosomeregions of thechrs. • Methylationpattern is transferredbycelldivisions • Mutation of MeCP2resultsdepression of genes to be methylated

  21. ! Duchennemusculardystrophy • X - Recessive • The most frequentmusculardystrophy • Duchennetype • onsetbefore 6 yrage • progressivemuscularweakness • heartmuscle is affected • ascendingcharacter • mentalretardation • pathological ECG and EMG • Se creatinin is increased • (decomposition of muscles) • Becker type • tarts in 20-30 yrage • descendingcharacter

  22. Duchennemusculardystrophy

  23. Incidence per 5000 live born male inherited spontaneous Duchennemusculardystrophy Incidence Spontáneous Inherited Females

  24. Birth Transient phase Inability of motion Terminal phase Freq. falls Muscular weakness Loss of functions Problems with respiration Infections Heart failures „Gower-maneuver”

  25. Xp21 ! Duchenne muscular dystrophy (2) 75 exons • Dystrophin gene mutation - Xp21 - this is the largest known gene – 2.300.000 bases (in size 12x factor VIII.; 15.000x beta globulin) - a mutations 70% deletion 20% point mutation 5% duplication - ~ 15-25% new mutations – without previous known appearence in the family - character of the mutations might influence the clinical progression

  26. Dystroglycan Sarcospan Sarcoglycans Membrane of myofibre Dystrophin/ Utrophin Pseudohypertrophia Syntrophins Actin Protein cluster Membrane of myofibre

  27. Membrane myofibre Beta-dystroglycan Dytrophin dystrophin Cytoskletális protein utrophin Utrophin is a potential replacement of the missing dystrophin !

  28. X fra(X) fra(X) Y Xq27.3 Fragile X syndrome (1) • Most frequent reason of mentális retardation • Clinical symptoms: • head is big, face is elongated, ears are big • mild – sever mental retardation • 1/3 of affected females has mental retardation • Xq27.3 – increased fragility

  29. ! • Mutation of Xq28 FRAXA gene – CGG trinucleotide-repeat • Expansion takes place at the „maternal- transfer” • Affected region is the gene 5’ region of the gene (not transcribed region) • Pathological elnogation is escorted by methylation which inhibits expression • FMR-1 protein is an RNA binding protein (fragile X mental retardation)

  30. 50-200 repeats CGG CGG CGG 5-50 repeats FMR-1 gene Healthy ‘Pre-mutation’ 200 - repeats ‘Full mutation’

  31. (CGG)n

  32. Fragile X syndrome (2) Prevalence: 1/200 male; 1/2500 female Incomplet penetrance Anticipation

  33. (huntingtin)

  34. + Y Chrs linked inheritance Guppi (Poecilia reticulata) Sexual attractivity vs. Increased defencelessness as a prey animal

  35. ! • Sex limited inheritance The trait is present in the genotype of both sex, however it is expressed only in one sex E.g. hair, menstruation, pelvic parameters

  36. X X X X X X X Y Y Y X X ! • Incomplet sex restriction Crossing over between pseudoautosomal regions of X and Y chrs.

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