Spinal Müsküler Atrofi ve Moleküler Genetiği

Sabriye Kocatürk Sel; Halil Kasap; Filiz Koç; Ali İrfan Güzel

Spinal Muscular Atrophy and Its Molecular Genetics

Yıl 2012, Cilt: 21 Sayı: 1, 1 - 26, 01.03.2012

Sabriye Kocatürk Sel Halil Kasap Filiz Koç Ali İrfan Güzel

Öz

Spinal muscular atrophy (SMA) is one of the most common autosomal recessive diseases, affecting aproximately 1 in 6,000 - 10,000 live births, and with a carrier frequency of aproximately 1 in 40- 60. The childhood SMAs can be classified clinically into three groups. Type I (Werdnig-Hoffmann) is the most severe form, with onset at ‹ 6 months of age and with death typically at ‹2 years of age. Type II SMA patients display an intermediate severity, with onset at ‹18 months of age and with an inability to walk. Type III (Kugelberg –Walender) individuals are able to walk independently and have a relatively mild phenotype, with onset at ›18 months of age. The gene involved in type I–III SMA has been mapped to 5q12-q13 by linkage analysis, and refined to a region of about 500 kb. The region contains a large inverted duplication consisting of at least four genes, which are present in a telomeric (t) and a centromeric (c) copy: survival motor neuron gene (SMN1 or SMNt and SMN2 or SMNc); neuronal apoptosis inhibitory protein gene (NAIP); basal transcription factor subunit p44 (BTFp44t and BTFp44c); and a novel protein with unknown function H4F5. Although homozygous deletions encompassing all these genes are found in SMA patients, it is now well established that mutations or deletions of SMN1 (MIM#600354) cause the disease. SMN2 (MIM# 601627) gene, however, does not prevent the disease but attenuates disease severity. Therefore, upregulating functional SMN protein level via inducing gene expression and/or restoring splicing is an important therapeutic approach such as use of histone deacetylase (HDAC) inhibitors.

Anahtar Kelimeler

HDAC inhibitors, SMA , SMN1, SMN2

Kaynakça

Monani et al., 1999 Monani et al., 1999 Monani et al., 1999 Monani et al., 1999 Monani et al., 1999 Monani et al., 1999 Monani et al., 1999 Monani et al., 1999 Monani et al., 1999 Monani et al., 1999 Monani et al., 1999 Monani et al., 1999 Monani et al., 1999
NAIP (Nöral Apoptozis İnhibitör Protein) Genomik uzunluğu 60 kb olan ve 16 ekzonu bulunan NAIP geni; 1232 amino asit uzunluğundaki 140 kD’luk bir proteini kodlar9. NAIP geni 1995 yılında SMA hastalarında delesyona uğrayan ikinci aday gen olarak tespit edilmiştir44. NAIP gen ekspresyonu doku özgüllüğü göstermez. Bu genin bir tam ve birden fazla kesikli kopyası vardır45. Hastalarda sadece tam kopyanın ve 6. ekzonlarında delesyon bulunması28,46nedeniyle delesyon analizi için tam kopyadaki ekzon 5 ve 6’nın multipleks PCR ile amplikasyonu yapılır ve delesyon varlığı araştırılır12.
SMA tip I grubunda yapılan 151. kodon ve 3’ucu 1939. nükleotid değişimi analizleri telomerik gende %53.5 oranında homozigot delesyon olduğunu göstermiştir12. Ancak, p44 geninde delesyon bulunduran hastaların tamamında SMN, bir kısmında da SMN ve NAIP genlerinde delesyon olması p44 genindeki mutasyonların hastalığın esas nedeni olmadığını düşündürmüştür. Bugüne kadar sadece p44 gen delesyonu bulunan bir SMA vakasının gösterilememiş olması genin tanı amaçlı olarak kullanılmasını ve önemini azaltmıştır12,27.
H4F5 ( SMA Modifiye Edici Gen 1) Scharf ve ark. tarafından 1998’de çok kopyalı mikrosatellit markır (C212) kullanılarak yapılan çalışmada, Tip I hastalarının %90’nında H4F5 gen bölgesinin delesyona uğradığı saptanmıştır. H4F5 geni tek başına SMA hastalığına yol açmazken hastalığın şiddeti üzerine etkili olmaktadır8,26,27.
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