Nonmendelian Nonmendelian KalıtımKalıtım: : DDiinaminamikk muta mutasysyononlarlar

Üçlü nukleotid tekrarları

Fragil X sendromu, Friedreich’s ataxia, Huntington’s hastalığı ve Myotonic distrofi

ObjectiObjectiflerfler

1991’de gözlendiler

Üçlü nukleotidlerde stabil olmayan artışlar izlendi

Tekrarlar normalde populasyonda polimorfik, fakat ailelerde stabil

Tekrarlar etkilenen ailelerde stabil değil

Artış çok farklı değerlerde olabilir

TarihçeTarihçe

14 14 stabil olmayanstabil olmayan TrinuTrinukkleotid leotid tekrarı ve tekrarı ve bunlarla ilgili hastalıklarbunlarla ilgili hastalıklar

AUGAUG TAATAA

CGGCGG GAAGAA CAGCAG CTGCTG

Fragil X SFragil X SeendromndromuuFragil XE MRFragil XE MR

Fredreich’s AtaxiaFredreich’s Ataxia

Spinobulbar Muscular AtrophySpinobulbar Muscular AtrophyHuntington’s DiseaseHuntington’s Disease

Dentatorubral-Pallidoluyslan AtrophyDentatorubral-Pallidoluyslan AtrophySpinocerebellar Ataxia Type 1Spinocerebellar Ataxia Type 1Spinocerebellar Ataxia Type 1Spinocerebellar Ataxia Type 1Spinocerebellar Ataxia Type 2Spinocerebellar Ataxia Type 2Spinocerebellar Ataxia Type 6Spinocerebellar Ataxia Type 6Spinocerebellar Ataxia Type 7Spinocerebellar Ataxia Type 7Spinocerebellar Ataxia Type 8Spinocerebellar Ataxia Type 8

Spinocerebellar Ataxia Type 12Spinocerebellar Ataxia Type 12Machado-Joseph Disease (SCA3)Machado-Joseph Disease (SCA3)

MyotoniMyotonikk D Diistrostrofifi

AUGAUG TAATAA

CGGCGG GAAGAA CAGCAG CTGCTG

Fragile X SyndromeFragile X SyndromeFragile XE MRFragile XE MR

Fredreich’s AtaxiaFredreich’s Ataxia

Spinobulbar Muscular AtrophySpinobulbar Muscular AtrophyHuntington’s DiseaseHuntington’s Disease

Dentatorubral-Pallidoluyslan AtropphyDentatorubral-Pallidoluyslan AtropphySpinocerebellar Ataxia Type 1Spinocerebellar Ataxia Type 1Spinocerebellar Ataxia Type 1Spinocerebellar Ataxia Type 1Spinocerebellar Ataxia Type 2Spinocerebellar Ataxia Type 2Spinocerebellar Ataxia Type 6Spinocerebellar Ataxia Type 6Spinocerebellar Ataxia Type 7Spinocerebellar Ataxia Type 7Spinocerebellar Ataxia Type 8Spinocerebellar Ataxia Type 8

Spinocerebellar Ataxia Type 12Spinocerebellar Ataxia Type 12Machado-Joseph Disease (SCA3)Machado-Joseph Disease (SCA3)

Myotonic DystrophyMyotonic Dystrophy

AUGAUG TAATAA

CGGCGG GAAGAA CAGCAG CTGCTG

5’ UTR5’ UTR

IntroniIntronikk

PolyglutaminePolyglutamine

Kodlama yapan Kodlama yapan bölgedebölgede

3’ UTR3’ UTR

Ortak özelliklerOrtak özellikler::Nörolojik hastalıkNörolojik hastalık

Genelde OGenelde Ototozzomal Dominant –X-omal Dominant –X-bağlıbağlı veyaveya re ressesesif olabilirlerif olabilirler

Azalmış penetransAzalmış penetrans gösterebilirlergösterebilirler

5’

5’

5’

Leading Strand Template

Lagging Strand Template

Okazaki Fragments

(A)

(B)Polymerization proceeds from 5’ to 3’ for the newly synthesized DNA strands. On the lagging strand, synthesis proceeds5’ to 3’ for each Okazaki fragment, but overall lagging strand synthesis proceeds 3’ to 5’ as the fragments extend, meet and are ligated together, indicated by 1,2,3.

23 1

3’

5’

3’

Slipped Mispairing underlies triplet repeat expansionSlipped Mispairing underlies triplet repeat expansion

5’

5’

5’

Leading Strand Template

Lagging Strand Template

Okazaki Fragments

(A)

(B)Polymerization proceeds from 5’ to 3’ for the newly synthesized DNA strands. On the lagging strand, synthesis proceeds5’ to 3’ for each Okazaki fragment, but overall lagging strand synthesis proceeds 3’ to 5’ as the fragments extend, meet and are ligated together, indicated by 1,2,3.

23 1

3’

5’

3’

Slipped Mispairing underlies triplet repeat expansionSlipped Mispairing underlies triplet repeat expansion

CG

GC

GG

CGGCGGCG

GC

GG

X-bağlı dominant penetrans azlığı gösterir

Orta düzeyde mental retardasyon – 1/4000 erkeklerde; 1/8000 dişilerde

X kromozomunda (Xq27.3) “fragil” bölge dekondanse

Fragil XFragil X

Fragil X Mental Retardasyon gen 1 FMR1

38 kb

AUG TAA

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

614 amino acids (69 kD)

(CGG)n

Klinik özellikler:Klinik özellikler: Fragil X Fragil X

Fragile X in malesFragile X in males

2 yrs. 5 yrs. 22 yrs.

Fragile X in femalesFragile X in females

Allel tipleri: Normal allel – 7-40 CGG Premutasyon allel - 60-200 Hasta allel - >200 den binlerce tekrara kadar

İşlev kaybı

Fragil XFragil X’de ’de CGG 5’ UTR CGG 5’ UTR dede FMR1 genFMR1 genindeinde

Fragil XFragil X

Premutation61-200 repeats

> 200 repeats, methylated

Common

Full mutation

41-60 repeats Intermediate

40 repeats

CpGIsland

(CGG)n5’ 3’

Transcription

Translation

Male Female

1/25 1/16

1/1000 1/350

1/4000 1/8000

FMR1 Repeat Instability

32P-CGG probe of PCR

500

94,25 85,25

86,2590

111

31

95 118 93

Premutation

Full mutation

Normal

I

II

III

mean

88

104

>230

NLS KH1 NES RGGKH2

111-152 206-280 281-422 425-441 527-552

Functional domains in the FMR protein

NLS-nuclear localization sequence (Eberhardt, et al. 1996. Hum.Mol.Gen)

KH-homology to hnRNP K (Siomi, et al. 1993. Cell)

NES-nuclear export sequence (Eberhardt, et al. 1996. Hum.Mol.Gen)

RGG-arginine-glycine-rich region (Siomi, et al. 1993. Cell)

Cytoplasmic protein

206-280 281-422111-152 425-441 527-552

Model for FMRP function in neuronsFMRP

AXON

DENTRITE

Glu

mGluR

Spine maturation; synaptic plasticity

otosomal recessive

spinocerebellar ataxia

Friedreich AtaxiaFriedreich Ataxia

www.barnstormers.org.uk/ images/jamie1.jpg

1/50,0001/50,000

AAG tekrarları intron frataxin de

Alel Tipleri: Normal allel - <34 tekrar Taşıyıcı allel – 36-100 tekrar Hasta allel - >100 tekrar

Friedreich AtaxiaFriedreich Ataxia

AUGAUG TAATAA

CGGCGG GAAGAA CAGCAG CTGCTG

Frataxin mitokondrial protein Demir metabolismasında iş görür.

Otosomal Dominant (~1/25,000,)

Orta yaşta başlar ölümle sonuçlanır.

Huntington Disease (HD)Huntington Disease (HD)

Atrophy of the caudate and Atrophy of the caudate and putamenputamen

polyglutamin-kodlayan gende CAG ekson 1de

Normalde – 9-35 CAG tekrar

Hastalarda – 36+ tekrar üstü 120 ye kadar.

HD CAGHD CAG tekrarı ile oluşur. tekrarı ile oluşur.

Solid line – avg age at onset; shaded area shows rage of age of onsetSolid line – avg age at onset; shaded area shows rage of age of onset

Artış mayozda oluşurArtış mayozda oluşur

Huntington Huntington HastalığıHastalığı ve ve Founder Founder (Kurucu) (Kurucu) etkisietkisi

MyotoniMyotonikk D Diistrostrofifi

CTG tekrarı 3’UTR DMPK geni (19q13) – bir protein kinase

Normal allel – 5-30 CTG tekrar

Orta – 50-80 tekrar

Klasik allel – 80-150 tekrar

Kongenital – 2,000+ tekrar

Myotonic Dystrophy CTG Myotonic Dystrophy CTG tekrarıtekrarı

Anticipation in Myotonic Anticipation in Myotonic DystrophyDystrophy

mildmild

classicclassic classicclassic

congenitalcongenital congenitalcongenital

60, 660, 6 5, 75, 7

90, 590, 5 96, 796, 7

2150, 122150, 12

4, 124, 12

2900, 42900, 4

Repeat size in DMPK geneRepeat size in DMPK gene

Üçlü nükleotid tekrarları hastalıklar oluşturabilir.

Myotonic Dystrophy

Huntington’s Disease

Fragile X Syndrome

Friedreich’s Ataxia

SonuçSonuç