دوره 32، شماره 293: هفته دوم شهریورماه 1393:1073-1080

بررسی جهش در اگزون‌های 8 و 3 ژن 1A3SLC و اگزون‌های 4 و 10 ژن 9A7 SLC در بیماران مبتلا به سیتینوری در ایران

لیلا كولیوند, مهرداد محمدی, رسول صالحی, بهروز عزت‌پور, مجید خیراللهی

چکیده


مقدمه: سسیستینوری یکی از اولین اختلالات متابولیسمی شناخته شده می‌باشد که با افزایش ترشح سیستین، آرژنین، لیزین و اورنیتین به درون ادرار مشخص می‌شود. دو ژن در ارتباط با بیماری شناخته شده است: ژن 1A3SLC (3/16p2) کد کننده‌ی زیر واحد سنگین rBAT، متعلق به ترانسپورتر کلیوی +,0b و ژن 9A7SLC (1/13q19) که زیر واحد سبک ترانسپورتر را کدگذاری می‌کند. بیماران با دو جهش در ژن 1A3SLC به عنوان نوع A، بیماران با دو جهش در ژن 9A7SLC به عنوان نوع B شناخته می‌شوند. بیماران با سیستینوری نوع AB دارای یک جهش در ژن 1A3SLC و یک جهش در ژن 9A7SLC می‌باشند. با وجود توزیع اختصاصی جهش در جمعیت‌های خاص، مطالعات محدودی در خاور میانه صورت گرفته است. این مطالعه نتایج بررسی ژنتیکی در بیماران مبتلا به سیستینوری در ایران را ارایه می‌دهد.

روش‌ها: 30 بیمار تحت عمل جراحی برداشت سنگ کلیه، توسط پزشک متخصص اورولوژیست با تشخیص سنگ‌ها‌ی سیستینی انتخاب شدند. بیماران برای تعیین جهش، با استفاده از روش‌های ARMS (Amplification refractory mutation system) و PCR-RFLP (Polymerase chain reaction-Restriction fragment length polymorphism) مورد بررسی قرار گرفتند.

یافته‌ها: در مجموع چند واریانت اعم از بد معنی، پلی‌مورفیسم، هم‌معنی و واریانت اینترونی یافت شدند؛ اما جهش‌های شایع مطالعات دیگر، در بیماران این مطالعه یافت نشدند.

نتیجه‌گیری: شاید بتوان این مطالعه را تأییدی بر اثر نژادی روی توزیع جهش‌ها در بیماری سیستینوری دانست. امید آن می‌رود که این مطالعه بتواند در درک ژنتیک مولکولی بیماران سیستینوری در ایران روشنگر باشد.

 


واژگان کلیدی


جهش؛ سیستینوری؛ ایران

تمام متن:

PDF

مراجع


Garrod AE. Inborn errors of metabolism (lectures I–IV). Lancet 1908; 2: 214–20.

Palacin M, Goodyear P, Nunes V, Gasparini P. Cystinuria. In: Scriver C, Baudet AL, Sly WS, Valle D, editors. The metabolic and molecular basis of inherited disease. 8th ed. New York, NY: McGraw-Hill; 2001.

Palacin M, Borsani G, Sebastio G. The molecular bases of cystinuria and lysinuric protein intolerance. Curr Opin Genet Dev 2001; 11(3): 328-35.

Tanzer F, Ozgur A, Bardakci F. Type I cystinuria and its genetic basis in a population of Turkish school children. Int J Urol 2007; 14(10): 914-7.

Saravakos P, Kokkinou V, Giannatos E. Cystinuria: current diagnosis and management. Urology 2014; 83(4): 693-9.

Knoll T, Zollner A, Wendt-Nordahl G, Michel MS, Alken P. Cystinuria in childhood and adolescence: recommendations for diagnosis, treatment, and follow-up. Pediatr Nephrol 2005; 20(1): 19-24.

Akhavan sepahi M, Sharifian M, Shajari A, Heidary A. Clinical manifestations and etiology of renal and urethra stone in children less than 14 years old referring to Fatemi-e-Sahamieh pediatric hospital in Qom, 2007-2008. J Arak Univ Med Sci 2009; 12(3): 1-7. [In Persian].

Feliubadalo L, Font M, Purroy J, Rousaud F, Estivill X, Nunes V, et al. Non-type I cystinuria caused by mutations in SLC7A9, encoding a subunit (bo,+AT) of rBAT. Nat Genet 1999; 23(1): 52-7.

Skopkova Z, Hrabincova E, Stastna S, Kozak L, Adam T. Molecular genetic analysis of SLC3A1 and SLC7A9 genes in Czech and Slovak cystinuric patients. Ann Hum Genet 2005; 69(Pt 5): 501-7.

Calonge MJ, Gasparini P, Chillaron J, Chillon M, Gallucci M, Rousaud F, et al. Cystinuria caused by mutations in rBAT, a gene involved in the transport of cystine. Nat Genet 1994; 6(4): 420-5.

Pras E, Raben N, Golomb E, Arber N, Aksentijevich I, Schapiro JM, et al. Mutations in the SLC3A1 transporter gene in cystinuria. Am J Hum Genet 1995; 56(6): 1297-303.

Eggermann T, Venghaus A, Zerres K. Cystinuria: an inborn cause of urolithiasis. Orphanet J Rare Dis 2012; 7: 19.

Wartenfeld R, Golomb E, Katz G, Bale SJ, Goldman B, Pras M, et al. Molecular analysis of cystinuria in Libyan Jews: exclusion of the SLC3A1 gene and mapping of a new locus on 19q. Am J Hum Genet 1997; 60(3): 617-24.

Barbosa M, Lopes A, Mota C, Martins E, Oliveira J, Alves S, et al. Clinical, biochemical and molecular characterization of cystinuria in a cohort of 12 patients. Clin Genet 2012; 81(1): 47-55.

Dello SL, Pras E, Pontesilli C, Beccia E, Ricci-Barbini V, de SL, et al. Comparison between SLC3A1 and SLC7A9 cystinuria patients and carriers: a need for a new classification. J Am Soc Nephrol 2002; 13(10): 2547-53.

Schmidt C, Vester U, Hesse A, Lahme S, Lang F, Zerres K, et al. The population-specific distribution and frequencies of genomic variants in the SLC3A1 and SLC7A9 genes and their application in molecular genetic testing of cystinuria. Urol Res 2004; 32(2): 75-8.

Font MA, Feliubadalo L, Estivill X, Nunes V, Golomb E, Kreiss Y, et al. Functional analysis of mutations in SLC7A9, and genotype-phenotype correlation in non-Type I cystinuria. Hum Mol Genet 2001; 10(4): 305-16.

Eggermann T, Spengler S, Wirth J, Lahme S. Molecular genetic testing in cystinuria. Int J Human Genet 2011; 11(1): 41-4.

Di PM, Louizou E, Fischetti L, Dedoussis GV, Stanziale P, Michelakakis H, et al. Twenty-four novel mutations identified in a cohort of 85 patients by direct sequencing of the SLC3A1 and SLC7A9 cystinuria genes. Genet Test 2008; 12(3): 351-5.

Shigeta Y, Kanai Y, Chairoungdua A, Ahmed N, Sakamoto S, Matsuo H, et al. A novel missense mutation of SLC7A9 frequent in Japanese cystinuria cases affecting the C-terminus of the transporter. Kidney Int 2006; 69(7): 1198-206.

Botzenhart E, Vester U, Schmidt C, Hesse A, Halber M, Wagner C, et al. Cystinuria in children: distribution and frequencies of mutations in the SLC3A1 and SLC7A9 genes. Kidney Int 2002; 62(4): 1136-42.

Chillaron J, Font-Llitjos M, Fort J, Zorzano A, Goldfarb DS, Nunes V, et al. Pathophysiology and treatment of cystinuria. Nat Rev Nephrol 2010; 6(7): 424-34.

Schmidt C, Albers A, Tomiuk J, Eggermann K, Wagner C, Capasso G, et al. Analysis of the genes SLC7A9 and SLC3A1 in unclassified cystinurics: mutation detection rates and association between variants in SLC7A9 and the disease. Clin Nephrol 2002; 57(5): 342-8.

Bisceglia L, Fischetti L, Bonis PD, Palumbo O, Augello B, Stanziale P, et al. Large rearrangements detected by MLPA, point mutations, and survey of the frequency of mutations within the SLC3A1 and SLC7A9 genes in a cohort of 172 cystinuric Italian patients. Mol Genet Metab 2010; 99(1): 42-52.

Chatzikyriakidou A, Sofikitis N, Georgiou I. Identification of novel cystinuria mutations and polymorphisms in SLC3A1 and SLC7A9 genes: absence of SLC7A10 gene mutations in cystinuric patients. Genet Test 2005; 9(3): 175-84.

Yuen YP, Lam CW, Lai CK, Tong SF, Li PS, Tam S, et al. Heterogeneous mutations in the SLC3A1 and SLC7A9 genes in Chinese patients with cystinuria. Kidney Int 2006; 69(1): 123-8.

Harnevik L, Fjellstedt E, Molbaek A, Denneberg T, Soderkvist P. Mutation analysis of SLC7A9 in cystinuria patients in Sweden. Genet Test 2003; 7(1): 13-20.

Chatzikyriakidou A, Sofikitis N, Giannakis D, Tsambalas S, Georgiou I. 466 Six novel polymorphic variants in SLC3A1 and SLC7A9 genes: New approaches to the study of cystinuria. European Urology Supplements 2004; 3(2): 119.

Raponi M, Baralle D. Alternative splicing: good and bad effects of translationally silent substitutions. FEBS J 2010; 277(4): 836-40.

Pagani F, Raponi M, Baralle FE. Synonymous mutations in CFTR exon 12 affect splicing and are not neutral in evolution. Proc Natl Acad Sci U S A 2005; 102(18): 6368-72.

Font-Llitjos M, Jimenez-Vidal M, Bisceglia L, Di PM, de SL, Rousaud F, et al. New insights into cystinuria: 40 new mutations, genotype-phenotype correlation, and digenic inheritance causing partial phenotype. J Med Genet 2005; 42(1): 58-68.

Schmidt C, Tomiuk J, Botzenhart E, Vester U, Halber M, Hesse A, et al. Genetic variations of the SLC7A9 gene: allele distribution of 13 polymorphic sites in German cystinuria patients and controls. Clin Nephrol 2003; 59(5): 353-9.

Chatzikyriakidou A, Louizou E, Dedousis GV, Bisceglia L, Michelakakis H, Georgiou I. An overview of SLC3A1 and SLC7A9 mutations in Greek cystinuria patients. Mol Genet Metab 2008; 95(3): 192-3.

Harnevik L, Fjellstedt E, Molbaek A, Tiselius HG, Denneberg T, Soderkvist P. Identification of 12 novel mutations in the SLC3A1 gene in Swedish cystinuria patients. Hum Mutat 2001; 18(6): 516-25.

Guillen M, Corella D, Cabello ML, Gonzalez JI, Sabater A, Chaves JF, et al. Identification of novel SLC3A1 gene mutations in Spanish cystinuria families and association with clinical phenotypes. Clin Genet 2005; 67(3): 240-51.

Gasparini P, Calonge MJ, Bisceglia L, Purroy J, Dianzani I, Notarangelo A, et al. Molecular genetics of cystinuria: identification of four new mutations and seven polymorphisms, and evidence for genetic heterogeneity. Am J Hum Genet 1995; 57(4): 781-8.

Endsley JK, Phillips JA, III, Hruska KA, Denneberg T, Carlson J, George AL, Jr. Genomic organization of a human cystine transporter gene (SLC3A1) and identification of novel mutations causing cystinuria. Kidney Int 1997; 51(6): 1893-9.

Egoshi KI, Akakura K, Kodama T, Ito H. Identification of five novel SLC3A1 (rBAT) gene mutations in Japanese cystinuria. Kidney Int 2000; 57(1): 25-32.

Bisceglia L, Calonge MJ, Dello SL, Rizzoni G, de SL, Gallucci M, et al. Molecular analysis of the cystinuria disease gene: identification of four new mutations, one large deletion, and one polymorphism. Hum Genet 1996; 98(4): 447-51.

Albers A, Lahme S, Wagner C, Kaiser P, Zerres K, Capasso G, et al. Mutations in the SLC3A1 gene in cystinuric patients: frequencies and identification of a novel mutation. Genet Test 1999; 3(2): 227-31.




Creative Commons Attribution-NonCommercial 4.0

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 Unported License which allows users to read, copy, distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited properly.