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