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

Year 2012, Volume: 47 Issue: 4, 278 - 282, 01.12.2012
https://doi.org/10.4274/tpa.838

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

References

  • Bao Y, Dawson TL Jr, Chen YT. Human glycogen debranching enzyme gene (AGL): complete structural organization and characterization of the 5' flanking region. Genomics 1996; 38(2): 155-65.
  • Kishnani PS, Austin SL, Arn P, et al. Glycogen storage disease type III diagnosis and management guidelines. Genet Med 2010; 12(7): 446-63.
  • Okubo M, Horinishi A, Nakamura N, et al. A novel point mutation in an acceptor splice site of intron 32 (IVS32 A-12-->G) but no exon 3 mutations in the glycogen debranching enzyme gene in a homozygous patient with glycogen storage disease type IIIb. Hum Genet 1998; 102(1): 1-5.
  • Shaiu WL, Kishnani PS, Shen J, Liu HM, Chen YT. Genotype-phenotype correlation in two frequent mutations and mutation update in type III glycogen storage disease. Mol Genet Metab 2000; 69(1): 16-23.
  • Horinishi A, Okubo M, Tang NL, et al. Mutational and haplotype analysis of AGL in patients with glycogen storage disease type III. J Hum Genet 2002; 47(2): 55-9.
  • Okubo M, Horinishi A, Takeuchi M, et al. Heterogeneous mutations in the glycogen-debranching enzyme gene are responsible for glycogen storage disease type IIIa in Japan. Hum Genet 2000; 106(1): 108-15.
  • Lucchiari S, Fogh I, Prelle A, et al. Clinical and genetic variability of glycogen storage disease type IIIa: seven novel AGL gene mutations in the Mediterranean area. Am J Med Genet 2002; 109(3): 183-90.
  • Lucchiari S, Santoro D, Pagliarani S, Comi GP. Clinical, biochemical and genetic features of glycogen debranching enzyme deficiency. Acta Myol 2007; 26(1): 72-4.
  • Endo Y, Fateen E, El Shabrawy M, et al. Egyptian glycogen storage
  • disease type III - identification of six novel AGL mutations, including a large 1.5 kb deletion and a missense mutation p.L620P with subtype IIId. Clin Chem Lab Med 2009; 47(10): 1233-8.
  • Okubo M, Spengos K, Manta P, Fateen E. Phenotypical variability in glycogen storage disease type III with a recurrent AGL mutation c.750- 753delAGAC. Muscle Nerve 2011; 43(3): 451.
  • Lam CW, Lee AT, Lam YY, et al. DNA-based subtyping of glycogen storage disease type III: mutation and haplotype analysis of the AGL gene in Chinese. Mol Genet Metab 2004; 83(3): 271-5.
  • Aoyama Y, Ozer I, Demirkol M, et al. Molecular features of 23 patients with glycogen storage disease type III in Turkey: a novel mutation p.R1147G associated with isolated glucosidase deficiency, along with 9 AGL mutations. J Hum Genet 2009; 54(11): 681-6.
  • Endo Y, Horinishi A, Vorgerd M, et al. Molecular analysis of the AGL gene: heterogeneity of mutations in patients with glycogen storage disease type III from Germany, Canada, Afghanistan, Iran, and Turkey. J Hum Genet 2006; 51(11): 958-63.
  • Parvari R, Moses S, Shen J, Hershkovitz E, Lerner A, Chen YT. A single-base deletion in the 3'-coding region of glycogen-debranching enzyme is prevalent in glycogen storage disease type IIIA in a population of North African Jewish patients. Eur J Hum Genet 1997; 5(5): 266-70.
  • Goldstein JL, Austin SL, Boyette K, et al. Molecular analysis of the AGL gene: identification of 25 novel mutations and evidence of genetic heterogeneity in patients with Glycogen Storage Disease Type III. Genet Med 2010; 12(7): 424-30.
  • Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988; 16: 215.
  • Kiechl S, Kohlendorfer U, Thaler C, et al. Different clinical aspects of debrancher deficiency myopathy. J Neurol Neurosurg Psychiatry 1999; 67: 364-8.
  • Coleman RA, Winter HS, Wolf B, Gilchrist JM, Chen YT. Glycogen storage disease type III (glycogen debranching enzyme deficiency): correlation of biochemical defects with myopathy and cardiomyopathy. Ann Intern Med 1992; 116: 896-900.
  • Endo Y, Fateen E, Aoyama Y, et al. Molecular characterization of Egyptian patients with glycogen storage disease type IIIa. J Hum Genet 2005; 50(10): 538-42.
  • Schoser B, Gläser D, Müller-Höcker J. Clinicopathological analysis of the homozygous p.W1327X AGL mutation in glycogen storage disease type 3. Am J Med Genet A 2008; 146A(22): 2911-5.
  • Aoyama Y, Endo Y, Ebara T, et al. Novel AGL mutation in a Turkish patient with glycogen storage disease type IIIa. Pediatr Int 2010; 52(1): 145-7.

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

Year 2012, Volume: 47 Issue: 4, 278 - 282, 01.12.2012
https://doi.org/10.4274/tpa.838

Abstract

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.

References

  • Bao Y, Dawson TL Jr, Chen YT. Human glycogen debranching enzyme gene (AGL): complete structural organization and characterization of the 5' flanking region. Genomics 1996; 38(2): 155-65.
  • Kishnani PS, Austin SL, Arn P, et al. Glycogen storage disease type III diagnosis and management guidelines. Genet Med 2010; 12(7): 446-63.
  • Okubo M, Horinishi A, Nakamura N, et al. A novel point mutation in an acceptor splice site of intron 32 (IVS32 A-12-->G) but no exon 3 mutations in the glycogen debranching enzyme gene in a homozygous patient with glycogen storage disease type IIIb. Hum Genet 1998; 102(1): 1-5.
  • Shaiu WL, Kishnani PS, Shen J, Liu HM, Chen YT. Genotype-phenotype correlation in two frequent mutations and mutation update in type III glycogen storage disease. Mol Genet Metab 2000; 69(1): 16-23.
  • Horinishi A, Okubo M, Tang NL, et al. Mutational and haplotype analysis of AGL in patients with glycogen storage disease type III. J Hum Genet 2002; 47(2): 55-9.
  • Okubo M, Horinishi A, Takeuchi M, et al. Heterogeneous mutations in the glycogen-debranching enzyme gene are responsible for glycogen storage disease type IIIa in Japan. Hum Genet 2000; 106(1): 108-15.
  • Lucchiari S, Fogh I, Prelle A, et al. Clinical and genetic variability of glycogen storage disease type IIIa: seven novel AGL gene mutations in the Mediterranean area. Am J Med Genet 2002; 109(3): 183-90.
  • Lucchiari S, Santoro D, Pagliarani S, Comi GP. Clinical, biochemical and genetic features of glycogen debranching enzyme deficiency. Acta Myol 2007; 26(1): 72-4.
  • Endo Y, Fateen E, El Shabrawy M, et al. Egyptian glycogen storage
  • disease type III - identification of six novel AGL mutations, including a large 1.5 kb deletion and a missense mutation p.L620P with subtype IIId. Clin Chem Lab Med 2009; 47(10): 1233-8.
  • Okubo M, Spengos K, Manta P, Fateen E. Phenotypical variability in glycogen storage disease type III with a recurrent AGL mutation c.750- 753delAGAC. Muscle Nerve 2011; 43(3): 451.
  • Lam CW, Lee AT, Lam YY, et al. DNA-based subtyping of glycogen storage disease type III: mutation and haplotype analysis of the AGL gene in Chinese. Mol Genet Metab 2004; 83(3): 271-5.
  • Aoyama Y, Ozer I, Demirkol M, et al. Molecular features of 23 patients with glycogen storage disease type III in Turkey: a novel mutation p.R1147G associated with isolated glucosidase deficiency, along with 9 AGL mutations. J Hum Genet 2009; 54(11): 681-6.
  • Endo Y, Horinishi A, Vorgerd M, et al. Molecular analysis of the AGL gene: heterogeneity of mutations in patients with glycogen storage disease type III from Germany, Canada, Afghanistan, Iran, and Turkey. J Hum Genet 2006; 51(11): 958-63.
  • Parvari R, Moses S, Shen J, Hershkovitz E, Lerner A, Chen YT. A single-base deletion in the 3'-coding region of glycogen-debranching enzyme is prevalent in glycogen storage disease type IIIA in a population of North African Jewish patients. Eur J Hum Genet 1997; 5(5): 266-70.
  • Goldstein JL, Austin SL, Boyette K, et al. Molecular analysis of the AGL gene: identification of 25 novel mutations and evidence of genetic heterogeneity in patients with Glycogen Storage Disease Type III. Genet Med 2010; 12(7): 424-30.
  • Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988; 16: 215.
  • Kiechl S, Kohlendorfer U, Thaler C, et al. Different clinical aspects of debrancher deficiency myopathy. J Neurol Neurosurg Psychiatry 1999; 67: 364-8.
  • Coleman RA, Winter HS, Wolf B, Gilchrist JM, Chen YT. Glycogen storage disease type III (glycogen debranching enzyme deficiency): correlation of biochemical defects with myopathy and cardiomyopathy. Ann Intern Med 1992; 116: 896-900.
  • Endo Y, Fateen E, Aoyama Y, et al. Molecular characterization of Egyptian patients with glycogen storage disease type IIIa. J Hum Genet 2005; 50(10): 538-42.
  • Schoser B, Gläser D, Müller-Höcker J. Clinicopathological analysis of the homozygous p.W1327X AGL mutation in glycogen storage disease type 3. Am J Med Genet A 2008; 146A(22): 2911-5.
  • Aoyama Y, Endo Y, Ebara T, et al. Novel AGL mutation in a Turkish patient with glycogen storage disease type IIIa. Pediatr Int 2010; 52(1): 145-7.
There are 22 citations in total.

Details

Primary Language Turkish
Subjects Health Care Administration
Journal Section Original Research
Authors

Esra Manguoğlu This is me

Vedat Uygun This is me

Figen Özkaya This is me

Güven Lüleci This is me

Reha Artan This is me

Sibel Berker This is me

Publication Date December 1, 2012
Published in Issue Year 2012 Volume: 47 Issue: 4

Cite

APA Manguoğlu, E., Uygun, V., Özkaya, F., Lüleci, G., et al. (2012). Glikojen depo hastalığı tip III tanılı 10 Türk olgunun mutasyon analizleri: dört yeni mutasyonun tanımlanması. Türk Pediatri Arşivi, 47(4), 278-282. https://doi.org/10.4274/tpa.838
AMA Manguoğlu E, Uygun V, Özkaya F, Lüleci G, Artan R, Berker S. Glikojen depo hastalığı tip III tanılı 10 Türk olgunun mutasyon analizleri: dört yeni mutasyonun tanımlanması. Türk Pediatri Arşivi. December 2012;47(4):278-282. doi:10.4274/tpa.838
Chicago Manguoğlu, Esra, Vedat Uygun, Figen Özkaya, Güven Lüleci, Reha Artan, and Sibel Berker. “Glikojen Depo hastalığı Tip III tanılı 10 Türk Olgunun Mutasyon Analizleri: Dört Yeni Mutasyonun tanımlanması”. Türk Pediatri Arşivi 47, no. 4 (December 2012): 278-82. https://doi.org/10.4274/tpa.838.
EndNote Manguoğlu E, Uygun V, Özkaya F, Lüleci G, Artan R, Berker S (December 1, 2012) Glikojen depo hastalığı tip III tanılı 10 Türk olgunun mutasyon analizleri: dört yeni mutasyonun tanımlanması. Türk Pediatri Arşivi 47 4 278–282.
IEEE E. Manguoğlu, V. Uygun, F. Özkaya, G. Lüleci, R. Artan, and S. Berker, “Glikojen depo hastalığı tip III tanılı 10 Türk olgunun mutasyon analizleri: dört yeni mutasyonun tanımlanması”, Türk Pediatri Arşivi, vol. 47, no. 4, pp. 278–282, 2012, doi: 10.4274/tpa.838.
ISNAD Manguoğlu, Esra et al. “Glikojen Depo hastalığı Tip III tanılı 10 Türk Olgunun Mutasyon Analizleri: Dört Yeni Mutasyonun tanımlanması”. Türk Pediatri Arşivi 47/4 (December 2012), 278-282. https://doi.org/10.4274/tpa.838.
JAMA Manguoğlu E, Uygun V, Özkaya F, Lüleci G, Artan R, Berker S. Glikojen depo hastalığı tip III tanılı 10 Türk olgunun mutasyon analizleri: dört yeni mutasyonun tanımlanması. Türk Pediatri Arşivi. 2012;47:278–282.
MLA Manguoğlu, Esra et al. “Glikojen Depo hastalığı Tip III tanılı 10 Türk Olgunun Mutasyon Analizleri: Dört Yeni Mutasyonun tanımlanması”. Türk Pediatri Arşivi, vol. 47, no. 4, 2012, pp. 278-82, doi:10.4274/tpa.838.
Vancouver Manguoğlu E, Uygun V, Özkaya F, Lüleci G, Artan R, Berker S. Glikojen depo hastalığı tip III tanılı 10 Türk olgunun mutasyon analizleri: dört yeni mutasyonun tanımlanması. Türk Pediatri Arşivi. 2012;47(4):278-82.