Sex linked Sex linked inheritance inheritance ? r. habil. Kőhidai László r. habil. Kőhidai László U, Dept. Genetics, Cell- & Immunobiology U, Dept. Genetics, Cell- & Immunobiology 014. 014.
Dec 18, 2015
Sex linked inheritanceSex linked inheritance
?
Dr. habil. Kőhidai LászlóDr. habil. Kőhidai LászlóSU, Dept. Genetics, Cell- & ImmunobiologySU, Dept. Genetics, Cell- & Immunobiology2014.2014.
X Chrs linked dominant X Chrs linked dominant inheritanceinheritance
General characteristicsGeneral characteristics Offspring of affected male (X’Y) and healthy female (XX):Offspring of affected male (X’Y) and healthy female (XX):
male - healthy (XY)male - healthy (XY) female – affected in 100% (X’X)female – affected in 100% (X’X)
Affected mother (X’X or X’X’): 50% of sons and Affected mother (X’X or X’X’): 50% of sons and daughters are hetero- or homozygotes for the daughters are hetero- or homozygotes for the dominant X alleldominant X allel
Diseases are expressed in more severe forms Diseases are expressed in more severe forms in affected males in affected males
Mela : 2x Female Mela : 2x Female
X Chrs linked recessive X Chrs linked recessive inheritanceinheritance
General characteristicsGeneral characteristics Expressed only in homozygote (X’X’) femalesExpressed only in homozygote (X’X’) females (~ autosomal recessive)(~ autosomal recessive)
Hemizygote male (X’Y) is similar to the homozygote femalesHemizygote male (X’Y) is similar to the homozygote females
Affected fathers (X’Y) dauther is heterozygote (X’X)Affected fathers (X’Y) dauther is heterozygote (X’X) „ „carrier”carrier” The trait reappears in the grandsons of the The trait reappears in the grandsons of the affected fathers – „criss-cross” inheritanceaffected fathers – „criss-cross” inheritance Male >> FemaleMale >> Female
X Chrs linked traits/diseases X Chrs linked traits/diseases (frequency)(frequency)
/10.000/10.000Color blindness (red-green)Color blindness (red-green) 800800
Fragile XFragile X 5 5
Duchenne muscular dystrophyDuchenne muscular dystrophy 3 3
Haemophilia AHaemophilia A 2 2
Haemophilia BHaemophilia B 0.3 0.3
X-linked ichtyosisX-linked ichtyosis 2 2
X-linked agammagglobulinaemiaX-linked agammagglobulinaemia 0.1 0.1
Amelogenesis imperfectaAmelogenesis imperfecta
X – DominantX – Dominant
Synthesis of enamel Synthesis of enamel (external layer of teeth)(external layer of teeth) is affectedis affected
Heterozygote female –Heterozygote female –columnar patterncolumnar pattern(X’X)(X’X)
Homozygote female and hemizygote male – sever clinical formsHomozygote female and hemizygote male – sever clinical forms
Genes affected: Pathological proteins Genes affected: Pathological proteins of enamelof enamel
AMELX AMELX Xp22.3-1Xp22.3-1 amelogeninamelogeninAMELYAMELY Yp11Yp11 amelogeninamelogenin
ENAM ENAM 4q13.34q13.3 enamelinenamelin (5%) (5%)MMP20MMP20 11q22.311q22.3 zománc metalloproteinase zománc metalloproteinase KLK-4 gKLK-4 g 19q13.419q13.4 kallikrein-related peptidase 4kallikrein-related peptidase 4
WDR72WDR72 15q21.315q21.3 WD repeat-containing WD repeat-containing protein 72protein 72
FAM83HFAM83H 8q24.38q24.3 ffamily with sequence amily with sequence similarity 83, member Hsimilarity 83, member H
TUFT1 TUFT1 1q211q21 ttuftelinuftelin4q214q21 ameloblastinameloblastin
Incontinentia pigmentiIncontinentia pigmenti(X-Dom.)(X-Dom.)
- Vesicles in the skinVesicles in the skin- Irregular melanin depositsIrregular melanin deposits and pigmentationand pigmentation- AlopeciaAlopecia- Dental dysordersDental dysorders - Mental retardation Mental retardation 30%30%- Affected retina Affected retina 30%30%
- Lethal in hemizygotesLethal in hemizygotes- Majority of patients is femaleMajority of patients is female
Vitamin D resistant ricketsVitamin D resistant rickets(X-Dom)(X-Dom)
Xp21-22Xp21-22- Growing of body is slower- Growing of body is slower- Symptomes of rickets- Symptomes of rickets- Se P - decreasedSe P - decreased
Frequency: 1/20.000Frequency: 1/20.000
Most frequent reason of mentális retardationMost frequent reason of mentális retardation Clinical symptoms:Clinical symptoms:
- head is big, face is elongated, ears are bighead is big, face is elongated, ears are big- mild – sever mental retardationmild – sever mental retardation- 1/3 of affected females has mental retardation1/3 of affected females has mental retardation
Xq27.3 – increased fragilityXq27.3 – increased fragility
X fra(X) fra(X) Y X fra(X) fra(X) Y
Fragile X syndrome (1)Fragile X syndrome (1)
Xq27.3Xq27.3
Mutation of Xq28 FRAXA gene –Mutation of Xq28 FRAXA gene –
CGG CGG trinucleotide-repeattrinucleotide-repeat
Expansion takes place at the Expansion takes place at the „maternal-„maternal- transfer”transfer”
Affected region is the gene 5’ region of Affected region is the gene 5’ region of the gene (not transcribed region) the gene (not transcribed region)
Pathological elnogation is escorted by Pathological elnogation is escorted by methylationmethylation which inhibits which inhibits
expressionexpression
FMR-1 protein is an RNA binding FMR-1 protein is an RNA binding protein protein ((ffragile X ragile X mmental ental rretardation) etardation)
CGGCGG
CGGCGG
5-50 repeats5-50 repeats
CGGCGG
50-200 repeats50-200 repeats
200 - repeats200 - repeats
HealthyHealthy
‘‘Pre-mutation’Pre-mutation’
‘‘Full mutation’Full mutation’
FMR-1 geneFMR-1 gene
Prevalence: 1/200 male; 1/2500 femalePrevalence: 1/200 male; 1/2500 female
Incomplet penetranceIncomplet penetrance
Anticipation Anticipation
Fragile X syndrome (2)Fragile X syndrome (2)
(huntingtin)
HemophiliaHemophilia(X-Rec)(X-Rec)
Deficiency of blood clottingDeficiency of blood clotting
Hemophilia AHemophilia A
Factor VIII. deficiencyFactor VIII. deficiency45% inversion (F8A)45% inversion (F8A)insertion of LINE-1 sequenceinsertion of LINE-1 sequence 6% antibodies are developed6% antibodies are developed
to factor VIIIto factor VIII
Xq28Xq28
26 exons26 exons9 kb9 kb
HemophiliaHemophilia(X-Rec)(X-Rec)
Hemophilia BHemophilia B
Factor IX. deficiencyFactor IX. deficiency(protease praecursor)(protease praecursor)
2% deletion2% deletion Insertion (ALU sequence)Insertion (ALU sequence)
Animal model: Irish SetterAnimal model: Irish Setter
Xq26.3-27.1Xq26.3-27.1
8 exons8 exons34 kb34 kb
Deficiency of blood clottingDeficiency of blood clotting
HemophiliaHemophilia
Color blindnessColor blindness(X-Rec)(X-Rec)
Cones of retina detect Cones of retina detect the three basic colorsthe three basic colors
All trans retinalAll trans retinal3D structure of 3D structure of
Opsin Opsin is changedis changed
SensationSensationof lightof light
Genes of Opsin:Genes of Opsin:BCPBCP 7q31-357q31-35RCPRCP Xq28Xq28GCPGCP Xq28Xq28
Xq28 Xq28
6 exons6 exons
GCP – RCP GCP – RCP 96%96% homology homology
GCP – BCP 43% homologyGCP – BCP 43% homology
RCP deficiencyRCP deficiency PROTANOPIAPROTANOPIAGCP deficiencyGCP deficiency DEUTERANOPIADEUTERANOPIABCP deficiencyBCP deficiency TRITANOPIATRITANOPIA
Color blindnessColor blindness
Males Females Males Females
Color blindnessColor blindness
Rett syndrome (1)Rett syndrome (1)
Developes only in femalesDevelopes only in females
Normal development lasts 6-18 months ageNormal development lasts 6-18 months age
Loss of speachLoss of speach
Balance and coordination problemsBalance and coordination problems
Microcephaly, ataxia, autismMicrocephaly, ataxia, autism
transient hyperventillationtransient hyperventillation
In the next phase the disease is more stable, In the next phase the disease is more stable,
and patients will reach adult ageand patients will reach adult age
Locus affected Xp28Locus affected Xp28 Mutations in gene Mutations in gene MeCP2MeCP2 The protein associates to the CpG bases of the The protein associates to the CpG bases of the methylated DNAmethylated DNA Methylation inhibits transcription of the geneMethylation inhibits transcription of the gene Methylation pattern is limited to some regions Methylation pattern is limited to some regions of the chrs. of the chrs. Methylation pattern is transferred by cell divisionsMethylation pattern is transferred by cell divisions Mutation of Mutation of MeCP2MeCP2 results results depressiondepression of genes of genes to be methylatedto be methylated
Rett syndrome (2)Rett syndrome (2)
X - RecessiveX - Recessive The most frequent muscular dystrophyThe most frequent muscular dystrophy Duchenne typeDuchenne type
- onset before 6 yr ageonset before 6 yr age- progressive muscular weaknessprogressive muscular weakness- heart muscle is affectedheart muscle is affected- ascending characterascending character- mental retardationmental retardation- pathological ECG and EMGpathological ECG and EMG- Se creatinin is increased (decomposition of muscles)Se creatinin is increased (decomposition of muscles)
Becker typeBecker type- tarts in 20-30 yr agetarts in 20-30 yr age- descending characterdescending character
Duchenne muscular dystrophyDuchenne muscular dystrophy
Duchenne muscular Duchenne muscular dystrophydystrophy
Duchenne Duchenne muscular muscular dystrophydystrophy
Incidence
Spontaneous
Inherited
Female
Incidence
inherited spontaneous
BirthBirth
Transient Transient phasephase
InabilityInability of motionof motion
Terminal Terminal phasephase
Freq. fallsFreq. fallsMuscular weaknessMuscular weaknessLoss of functionsLoss of functions
Problems with Problems with respirationrespirationInfectionsInfectionsHeart failuresHeart failures
„„Gower-maneuver”Gower-maneuver”
Dystrophin gene mutationDystrophin gene mutation- Xp21- Xp21- this is the largest known gene – - this is the largest known gene – 2.300.0002.300.000 bases bases
(in size 12x factor VIII.; 15.000x beta globulin)(in size 12x factor VIII.; 15.000x beta globulin)
- a mutations - a mutations 70% deletion70% deletion20% point mutation20% point mutation 5% duplication5% duplication
- ~ - ~ 15-25% new mutations15-25% new mutations – without previous known – without previous known appearence in the familyappearence in the family
- character of the mutations might influence - character of the mutations might influence the clinical progression the clinical progression
Duchenne muscular dystrophy (2)Duchenne muscular dystrophy (2)
Xp21 Xp21 75 exons75 exons
Actin Actin
Dystrophin/ UtrophinDystrophin/ Utrophin
Syntrophins Syntrophins
SarcoglycansSarcoglycans
DystroglycanDystroglycan Sarcospan Sarcospan
Membrane of myofibre Membrane of myofibre
Protein clusterProtein cluster Membrane of myofibre Membrane of myofibre
dystrophindystrophin
utrophinutrophin
Membrane myofibre Membrane myofibre
Dytrophin Dytrophin
Cytoskletálisprotein
Cytoskletálisprotein
Beta-dystroglycanBeta-dystroglycan
UtrophinUtrophin is a potential replacement of the missing dystrophin ! is a potential replacement of the missing dystrophin !
Y Chrs linked inheritanceY Chrs linked inheritance
Guppi (Guppi (Poecilia reticulataPoecilia reticulata))
+
Sexual attractivity Sexual attractivity vs.vs.
Increased defencelessness as a prey animalIncreased defencelessness as a prey animal
Sex limited inheritanceSex limited inheritance
The trait is present in the genotype of both The trait is present in the genotype of both sex, however it is expressed only in one sex sex, however it is expressed only in one sex
E.g. hair, menstruation, pelvic parametersE.g. hair, menstruation, pelvic parameters
Incomplet sex restrictionIncomplet sex restriction
Crossing over between pseudoautosomal Crossing over between pseudoautosomal regions of X and Y chrs. regions of X and Y chrs.
XX XX
XX YY
XX YY XX YY XX XX
XX XX
Sex controlled inheritanceSex controlled inheritance
The trait is expressed in both sex, however its The trait is expressed in both sex, however its degree is differentdegree is different
Normal features:Normal features:
Deepness of soundDeepness of sound
BaldnessBaldness
BBBB++
BB++BB++
Male-baldness (androgenes)Male-baldness (androgenes)Female– normalFemale– normal
Male and Female - baldnessMale and Female - baldness
Diseases:Diseases:
gout 80% Mgout 80% MCleft lip/palateCleft lip/palate
Anencephaly - FAnencephaly - FSpina bifidaSpina bifida
www.biology.arizona.edu/mendelian_genetics/problem_sets/www.biology.arizona.edu/mendelian_genetics/problem_sets/
www.wwnorton.com/cdly/genetics/ch13quiz.htmwww.wwnorton.com/cdly/genetics/ch13quiz.htm
www.bbc.co.uk/health/genes/disorders/xlinked_2.shtmlwww.bbc.co.uk/health/genes/disorders/xlinked_2.shtml