Mutational analysis of ten Turkish patients with glycogen storage disease type III: identification of four novel mutations

Abstract

Aim: AGL gene mutations are responsible for glycogen storage disease type III which is an autosomal recessive disorder The distribution of these mutations shows a great variance in different populations The aim of this study is to uncover the AGL gene mutation profile among Turkish patients and to contribute to the establishment of a link between these mutations and the clinical picture of the disease Material and Method: A total of ten patients aged between two and eight years mean age 1 7 1 1 who were diagnosed with glycogen storage disease type III by liver biopsy and enzymatic analysis from eight different families were included in this study DNA was isolated from the peripheral blood samples of these patients and exons 6 7 9 18 22 24 29 34 of the AGL gene were studied by DNA sequencing analysis Results: Our study revealed two novel missense mutations p G167V and p Y173F two novel intronic single base substitutions c 1284 1G gt;A and c 2002 2A gt;T and a known single base substitution p W1327X Numerous intronic variants were also identified As a result of the analysis of ten patients SNP rsquo;s rs3736296 IVS12 197T gt;G rs2291637 rs2035961 rs2274570 rs6692695 rs296885 were found in 1 6 1 1 1 1 and 2 of the 10 patients respectively Conclusions: According to the recent literature about the AGL gene which is constituted of a total of 35 coding exons mutations have been reported frequently in exons 3 4 7 16 21 25 30 and 31 This study and previous studies reveal that the majority of the mutations identified in Turkish patients so far have been detected in exon 31 of the AGL gene In addition the distribution of AGL gene mutations in Turkish patients reflects the genetic heterogeneity in our population Turk Arch Ped 2012; 47: 278 82

Keywords

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Glikojen depo hastalığı tip III tanılı 10 Türk olgunun mutasyon analizleri: dört yeni mutasyonun tanımlanması

Öz

Amaç: Otozomal çekinik olarak kalıtılan Glikojen depo hastalığı tip III rsquo;den AGL gen mutasyonları sorumlu olmakla birlikte mutasyonların dağılımı toplumlara göre değişkenlik göstermektedir Bu çalışmanın amacı glikojen depo hastalığı tip III tanısı almış bireylerde toplumumuza özgü AGL gen mutasyonlarının belirlenmesine ve belirlenen mutasyonlarla hastalığın kliniği arasında ilişki kurulmasına katkıda bulunmaktır. 

Gereç ve Yöntem: Karaciğer biyopsisi yapılmış ve enzimatik analizlerle glikojen depo hastalığı tip III tanısı almış sekiz farklı aileden yaşları iki ile sekiz arasında ortalama yaş 1 7 1 1 olan toplam 10 hasta bu çalışmaya dahil edilmiştir Bu hastaların periferik kan örneklerinden DNA rsquo;ları elde edilmiş ve AGL geninin 6 7 9 18 22 24 29 34 numaralı ekzonları DNA dizi analizi ile incelenmiştir. 

Bulgular: Çalışmamızda iki yeni yanlış anlamlı mutasyon p G167V ve p Y173F iki yeni intronik bölgede tek baz değişimi c 1284 1G gt;A ve c 2002 2A gt;T ile daha önceden bilinen tek baz değişimi p W1327X saptanmıştır Ek olarak çok sayıda intronik bölge varyantları bulunmuştur Bunların dışında bazı tek nükleotid değişimleri de belirlenmiştir On hastanın analizi sonucunda rs3736296 rs2291637 rs2035961 rs2274570 rs6692695 değişimleri sadece birer kez gözlenirken 10 hastanın altısında IVS12 197T gt;G değişimi 10 hastanın ikisinde ise rs296885 değişimi saptanmıştır. 

Çıkarımlar: Genel olarak toplam 35 kodlayıcı ekzondan oluşan AGL geninin literatüre gore 3 4 7 16 21 25 30 ve 31 numaralı ekzonlarında sıklıkla mutasyonlar bildirilmiş olup bu çalışmanın sonuçları ve toplumumuzla ilgili diğer çalışmalar birlikte değerlendirildiğinde Türk olgularda şimdiye kadar tanımlanan mutasyonların büyük bölümünün AGL geninin 31 numaralı ekzonunda bulunduğu gözlenmiştir Bunun yanı sıra Türk hastalarda AGL gen mutasyonlarının dağılımı toplumumuzdaki genetik heterojeniteyi yansıtmaktadır.

Anahtar Kelimeler

• AGLgeni
• glikojen depo hastalığı tip III
• mutasyon

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