Nonmendelian Kalıtım: Dinamik mutasyonlar

Objectifler Üçlü nukleotid tekrarları Fragil X sendromu, Friedreich’s ataxia, Huntington’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 AUG TAA CGG GAA CAG CTG Fragil X Sendromu Fragil XE MR Fredreich’s Ataxia Spinobulbar Muscular Atrophy Huntington’s Disease Dentatorubral-Pallidoluyslan Atrophy Spinocerebellar Ataxia Type 1 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

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

CGG CAG CTG GAA Ortak özellikler: Nörolojik hastalık AUG TAA CGG CAG CTG GAA 5’ UTR Intronik Polyglutamine Kodlama yapan bölgede 3’ UTR 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 3’ 3 2 1 5’ 5’ (B) Okazaki Fragments 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’

Slipped Mispairing underlies triplet repeat expansion Lagging Strand Template 5’ Leading Strand Template (A) 3’ CGG CGG 3 CGG 2 1 5’ 5’ (B) Okazaki Fragments 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’

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 3 8 k b A U G T 1 2 4 5 6 7 9 a m i n o c d s ( D ) (CGG)n

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

Fragil X (CGG) n Transcription CpG Island Translation 5’ 3’  40 repeats Common Male Female 1/25 1/16 1/1000 1/350 1/4000 1/8000 41-60 repeats Intermediate 61-200 repeats Premutation > 200 repeats, methylated Full mutation

FMR1 Repeat Instability mean I 85,25 88 94,25 90 86,25 II 104 111 95 118 93 III >230 500 31 Full mutation Premutation Normal 32P-CGG probe of PCR

Functional domains in the FMR protein NLS KH1 KH2 NES RGG 111-152 206-280 281-422 425-441 111-152 206-280 281-422 425-441 527-552 527-552 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)

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

Friedreich Ataxia 1/50,000 otosomal recessive spinocerebellar ataxia 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 AUG TAA CGG CAG CTG GAA

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 mild Repeat size in DMPK gene 60, 6 5, 7 classic classic 90, 5 96, 7 4, 12 congenital congenital 2150, 12 2900, 4

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