Nonmendelian Kalitim: Dinamik mutasyonlar

1
Nonmendelian Kalitim Dinamik mutasyonlar
2
Objectifler

• Üçlü nukleotid tekrarlari
• Fragil X sendromu, Friedreichs ataxia,
  Huntingtons hastaligi ve Myotonic distrofi

3
Tarihçe

• 1991de gözlendiler
• Üçlü nukleotidlerde stabil olmayan artislar
  izlendi
• Tekrarlar normalde populasyonda polimorfik,
  fakat ailelerde stabil
• Tekrarlar etkilenen ailelerde stabil degil
• Artis çok farkli degerlerde olabilir

4
14 stabil olmayan Trinukleotid tekrari ve
bunlarla ilgili hastaliklar
5
AUG
TAA
CGG
CAG
CTG
GAA
Myotonic Dystrophy
Fredreichs Ataxia
Fragile X Syndrome Fragile XE MR
Spinobulbar Muscular Atrophy Huntingtons
Disease Dentatorubral-Pallidoluyslan
Atropphy Spinocerebellar Ataxia Type
1 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)
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AUG
TAA
CGG
CAG
CTG
GAA
7
Slipped Mispairing underlies triplet repeat
expansion
Lagging Strand Template
5
(A)
Leading Strand Template
3
2
3
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.
5
3
8
Slipped Mispairing underlies triplet repeat
expansion
Lagging Strand Template
5
Leading Strand Template
(A)
3
CGG
CGG
CGG
2
3
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.
5
3
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Fragil X

• X-bagli dominant penetrans azligi gösterir
• Orta düzeyde mental retardasyon 1/4000
  erkeklerde 1/8000 disilerde
• X kromozomunda (Xq27.3)
  fragil bölge dekondanse

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Fragil X Mental Retardasyon gen 1 FMR1
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Klinik özellikler Fragil X

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

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Fragile X in males
13
Fragile X in females
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Fragil Xde CGG 5 UTR de FMR1 geninde

• Allel tipleri
• Normal allel 7-40 CGG
• Premutasyon allel - 60-200
• Hasta allel - gt200 den binlerce tekrara kadar
• Islev kaybi

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Fragil X
Transcription
CpG Island
Translation
(CGG)
n
3
5
Common
? 40 repeats
41-60 repeats
Intermediate
Premutation
61-200 repeats
gt 200 repeats, methylated
Full mutation
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FMR1 Repeat Instability
mean
I
88
85,25
94,25
90
86,25
104
II
111
95 118 93
III
gt230
500
31
Full mutation
Premutation
Normal
32P-CGG probe of PCR
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Functional domains in the FMR protein
NLS
KH1
NES
RGG
KH2
206-280
281-422
111-152
425-441
527-552
111-152
206-280
281-422
425-441
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)
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Model for FMRP function in neurons
AXON
DENTRITE
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Friedreich Ataxia
1/50,000

• otosomal recessive
• spinocerebellar ataxia

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

• AAG tekrarlari intron frataxin de
• Alel Tipleri
• Normal allel - lt34 tekrar
• Tasiyici allel 36-100 tekrar
• Hasta allel - gt100 tekrar

AUG
TAA
CGG
CAG
CTG
GAA
21
Frataxin mitokondrial protein Demir
metabolismasinda is görür.
22
Huntington Disease (HD)

• Otosomal Dominant (1/25,000,)
• Orta yasta baslar ölümle sonuçlanir.

23
Atrophy of the caudate and putamen
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HD CAG tekrari ile olusur.

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

25
(No Transcript)
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Artis mayozda olusur
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Huntington Hastaligi ve Founder (Kurucu) etkisi
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Myotonik Distrofi
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Myotonic Dystrophy CTG tekrari

• CTG tekrari 3UTR 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

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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
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Sonuç

• Üçlü nükleotid tekrarlari hastaliklar
  olusturabilir.
• Myotonic Dystrophy
• Huntingtons Disease
• Fragile X Syndrome
• Friedreichs Ataxia