Nonmendelian Kalıtım:

Dinamik mutasyonlar

Objectifler

Üçlü nukleotid tekrarları Fragil X sendromu, F riedreich’s ataxia, H untington’s hastalığı ve Myotonic distrofi

Tarihçe

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

14 stabil olmayan Trinukleotid tekrarı ve bunlarla ilgili hastalıklar

CGG

AUG

GAA CAG

TAA

CTG

Fredreich’s Ataxia Fragil X Sendromu Fragil XE MR Spinobulbar Muscular Atrophy Huntington’s Disease Spinocerebellar Ataxia Type 2 Spinocerebellar Ataxia Type 6 Spinocerebellar Ataxia Type 7 Spinocerebellar Ataxia Type 8 Spinocerebellar Ataxia Type 12 Machado-Joseph Disease (SCA3) Myotonik Distrofi Dentatorubral-Pallidoluyslan Atrophy Spinocerebellar Ataxia Type 1 Spinocerebellar Ataxia Type 1

CGG

AUG

GAA CAG

TAA

CTG

Fredreich’s Ataxia Fragile X Syndrome Fragile XE MR Spinobulbar Muscular Atrophy Huntington’s Disease Spinocerebellar Ataxia Type 2 Spinocerebellar Ataxia Type 6 Myotonic Dystrophy Dentatorubral-Pallidoluyslan Atropphy Spinocerebellar Ataxia Type 1 Spinocerebellar Ataxia Type 1 Spinocerebellar Ataxia Type 7 Spinocerebellar Ataxia Type 8 Spinocerebellar Ataxia Type 12 Machado-Joseph Disease (SCA3)

CGG

AUG

GAA CAG

TAA

CTG

Intronik 3’ UTR 5’ UTR Polyglutamine Kodlama yapan bölgede

Ortak özellikler: Nörolojik hastalık Genelde Otozomal Dominant –X-bağlı veya resesif olabilirler Azalmış penetrans gösterebilirler

Slipped Mispairing underlies triplet repeat expansion

Lagging Strand Template 5’ (A) Leading Strand Template 5’ 3 2

Polymerization proceeds from 5’ to 3’ for the newly synthesized DNA strands. On the lagging strand, synthesis proceeds 5’ 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.

3’ 5’ Okazaki Fragments (B) 3’ 5’

Slipped Mispairing underlies triplet repeat expansion

Lagging Strand Template 5’ Leading Strand Template (A) 5’ 3 2

Polymerization proceeds from 5’ to 3’ for the newly synthesized DNA strands. On the lagging strand, synthesis proceeds 5’ 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.

3’ 5’ Okazaki Fragments (B) 3’ 5’

Fragil X

X bağlı dominant penetrans azlığı gösterir Orta düzeyde mental retardasyon – 1/4000 erkeklerde; 1/8000 dişilerde X kromozomunda (Xq27.3) “fragil” bölge dekondanse

Fragil X Mental Retardasyon gen 1

FMR1

(CGG) n AUG 1 614 amino acids (69 kD) TAA 2 3 4 5 6 7 8 38 kb 9 10 11 12 13 14 15 16 17

Klinik özellikler: Fragil X

Uzun yüz – Büyük kulaklar Mental gerilik (I.Q. 20-60) Dikkat kusuru/hiperaktivite

Fragile X in males

2 yrs.

5 yrs.

22 yrs.

Fragile X in females

Fragil X’de CGG 5’ UTR de FMR1 geninde

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

5’

Fragil X

CpG Island Transcription

(CGG)

n Translation

3’



40 repeats 41-60 repeats Common Intermediate Male 1/25 61-200 repeats > 200 repeats, methylated Premutation Full mutation 1/1000 1/4000 Female 1/16 1/350 1/8000

FMR1 Repeat Instability

94,25 500 86,25 90 85,25 111 31 95 118 93

Full mutation

I II III mean 88 104 >230

Premutation Normal 32 P-CGG probe of PCR

Functional domains in the FMR protein NLS KH1 KH2 NES RGG Cytoplasmic 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)

AXON FMRP Model for FMRP function in neurons DENTRITE mGluR Glu Spine maturation; synaptic plasticity

Friedreich Ataxia

otosomal recessive spinocerebellar ataxia 1/50,000 www.barnstormers.org.uk/ images/jamie1.jpg

Friedreich Ataxia

AAG tekrarları intron frataxin de Alel Tipleri:   Normal allel - <34 tekrar Taşıyıcı allel – 36-100 tekrar  Hasta allel - >100 tekrar CGG

AUG

GAA CAG

TAA

CTG

Frataxin mitokondrial protein Demir metabolismasında iş görür.

Huntington Disease (HD)

Otosomal Dominant (~1/25,000,) Orta yaşta başlar ölümle sonuçlanır.

Atrophy of the caudate and putamen

HD CAG tekrarı ile oluşur.

polyglutamin-kodlayan gende CAG ekson 1de Normalde – 9-35 CAG tekrar Hastalarda – 36+ tekrar üstü 120 ye kadar.

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

Artış mayozda oluşur

Huntington Hastalığı ve Founder (Kurucu) etkisi

Myotonik Distrofi

Myotonic Dystrophy CTG tekrarı

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

Anticipation in Myotonic Dystrophy

Repeat size in DMPK gene

mild

60, 6 5, 7

classic

90, 5

classic

96, 7 4, 12

congenital

2150, 12

congenital

2900, 4

Sonuç

Üçlü nükleotid tekrarları hastalıklar oluşturabilir. Myotonic Dystrophy Huntington’s Disease Fragile X Syndrome Friedreich’s Ataxia