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Nonmendelian Nonmendelian KalıtımKalıtım: : DDiinaminamikk muta mutasysyononlarlar
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Üçlü nukleotid tekrarları
Fragil X sendromu, Friedreich’s ataxia, Huntington’s hastalığı ve Myotonic distrofi
ObjectiObjectiflerfler
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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
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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
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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
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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
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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
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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
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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
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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
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Klinik özellikler:Klinik özellikler: Fragil X Fragil X
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Fragile X in malesFragile X in males
2 yrs. 5 yrs. 22 yrs.
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Fragile X in femalesFragile X in females
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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
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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
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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
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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
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Model for FMRP function in neuronsFMRP
AXON
DENTRITE
Glu
mGluR
Spine maturation; synaptic plasticity
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otosomal recessive
spinocerebellar ataxia
Friedreich AtaxiaFriedreich Ataxia
www.barnstormers.org.uk/ images/jamie1.jpg
1/50,0001/50,000
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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
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Frataxin mitokondrial protein Demir metabolismasında iş görür.
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Otosomal Dominant (~1/25,000,)
Orta yaşta başlar ölümle sonuçlanır.
Huntington Disease (HD)Huntington Disease (HD)
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Atrophy of the caudate and Atrophy of the caudate and putamenputamen
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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.
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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
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Artış mayozda oluşurArtış mayozda oluşur
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Huntington Huntington HastalığıHastalığı ve ve Founder Founder (Kurucu) (Kurucu) etkisietkisi
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MyotoniMyotonikk D Diistrostrofifi
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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
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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
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Üçlü nükleotid tekrarları hastalıklar oluşturabilir.
Myotonic Dystrophy
Huntington’s Disease
Fragile X Syndrome
Friedreich’s Ataxia
SonuçSonuç