Mukopolisakkaridoz Tip I (MPS I) hastalarında IDUA gen mutasyonlarının analizi
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Tarih
2013
Yazarlar
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Cilt Başlığı
Yayıncı
Aksaray Üniversitesi Fen Bilimleri Enstitüsü
Erişim Hakkı
info:eu-repo/semantics/openAccess
Özet
MPS Tip I hastalığı IDUA geni tarafından kodlanan ?-L-iduronidaz enziminin eksikliği nedeniyle ortaya çıkmaktadır. Bu tez çalışmasında klinik olarak MPS Tip I tanısı almış olan 15 hastada tanıyı moleküler düzeyde kesinleştirmek ve hastalığa neden olan IDUA genindeki mevcut mutasyonları belirlemek amacıyla DNA dizi analizi yapılmıştır. Hastalardan 10'unda, 3 yanlış anlamlı (p.M1L, p.A327P, p.P533L), 3 anlamsız (p.Y64X, p.W402X, p.R628X) ve üç kırpılma (c.494-1G>A, c.793-6C>G, c.793-5C>A) mutasyonu olmak üzere, toplam 9 farklı IDUA gen mutasyonu saptanmıştır. Bu mutasyonlardan 7'si farklı toplumlarda daha önce rapor edilmiş, 2'si ise (c.793-6C>G, c.793-5C>A) ilk kez bu çalışma kapsamında bulunmuştur. Hastalardan 9'u mutasyonları homozigot, 1'i birleşik heterozigot durumda taşımaktadır. Yeni varyasyonların enzim aktivitesi üzerine zararlı etkisinin olduğu 2 farklı analiz programı kullanılarak tespit edilmiştir. Klinik belirtilerine göre MPS Tip I tanısı almış olmalarına karşın, 5 hastaya ait DNA dizi analizi sonucunda hastalık nedeni olabilecek herhangi bir mutasyonun bulunamaması ve ?-L-iduronidaz enzim analiz sonuçlarının olmayışı nedeniyle bu hastaların farklı bir MPS tipine ait oldukları düşünülmüştür. Ayrıca, taranan hastalardan 3'ünde daha önce tanımlanmış olan 7 farklı IDUA gen polimorfizmi (p.A8A, p.A20A, p.H33Q, p.R105Q, p.A314A, p.T410T ve IVS5-8C>T) belirlenmiştir. Sonuç olarak ön tanısı MPS Tip I olan 15 hastadan 10'unda DNA dizi analizi ile klinik tanı moleküler düzeyde doğrulanarak, farklı mutant alleler saptanmıştır.
MPS Type I resulted from a lack of ? -L- iduronidase enzyme encoded by IDUA gene. In this study, 15 patients clinically diagnosed with MPS Type I were screened using DNA sequence analysis to confirm of diagnosis at the molecular level and to identify disease-causing IDUA gene mutations. Ten of screened patients have 9 different IDUA gene mutations which of three ( p.M1L , p.A327P , p.P533L ) were missense, three ( p.Y64X , p.W402X , p.R628X ) were nonsense and three (c.494-1G > A, c.793-6C > G, c.793-5C > A) were splicing one. Seven of these mutations have already been reported in different populations and two are novel (c.793-6C > G, c.793-5C > A). Nine patients have carried the mutations as homozygous and one has it in compound heterozygous state. A putative deleterious effect of novel mutations on protein function has detected using two different computational programs. Even 5 patients have diagnosed with MPS Type I according to their clinical symptoms, absence of ?-L-iduronidase enzyme analyses results and having no disease causing IDUA gene mutations means these patients may have different MPS type. Meanwhile, 7 different previously described IDUA gene polymorphism (p.A8A, p.A20A, p.H33Q, p.R105Q, p.A314A, p.T410T and IVS5-8C > T) are determined in 3 of screened patients. Consequently, clinical diagnosis was verified at the molecular level using DNA sequence analysis and 10 of 15 patients with the diagnosis of MPS type I had different IDUA gene mutant alleles.
MPS Type I resulted from a lack of ? -L- iduronidase enzyme encoded by IDUA gene. In this study, 15 patients clinically diagnosed with MPS Type I were screened using DNA sequence analysis to confirm of diagnosis at the molecular level and to identify disease-causing IDUA gene mutations. Ten of screened patients have 9 different IDUA gene mutations which of three ( p.M1L , p.A327P , p.P533L ) were missense, three ( p.Y64X , p.W402X , p.R628X ) were nonsense and three (c.494-1G > A, c.793-6C > G, c.793-5C > A) were splicing one. Seven of these mutations have already been reported in different populations and two are novel (c.793-6C > G, c.793-5C > A). Nine patients have carried the mutations as homozygous and one has it in compound heterozygous state. A putative deleterious effect of novel mutations on protein function has detected using two different computational programs. Even 5 patients have diagnosed with MPS Type I according to their clinical symptoms, absence of ?-L-iduronidase enzyme analyses results and having no disease causing IDUA gene mutations means these patients may have different MPS type. Meanwhile, 7 different previously described IDUA gene polymorphism (p.A8A, p.A20A, p.H33Q, p.R105Q, p.A314A, p.T410T and IVS5-8C > T) are determined in 3 of screened patients. Consequently, clinical diagnosis was verified at the molecular level using DNA sequence analysis and 10 of 15 patients with the diagnosis of MPS type I had different IDUA gene mutant alleles.
Açıklama
Anahtar Kelimeler
Mukopolisakkaridoz Tip I, Mutasyon Taraması, IDUA Geni, ?L-iduronidaz Enzimi, Mucopolysaccharidosis Type I, Mutation Screening, IDUA gene, ?-L iduronidase Enzyme
