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Title: Identification of 16 novel mutations in the argininosuccinate synthetase gene and genotype-phenotype correlation in 38 classical citrullinemia patients
Authors: Hong Zhi Gao
Keiko Kobayashi
Ayako Tabata
Hideaki Tsuge
Mikio Iijima
Tomotsugu Yasuda
H. Serap Kalkanoglu
Ali Dursun
Aysegul Tokatli
Turgay Coskun
Friedrich K. Trefz
Daniela Skladal
Hanna Mandel
Joerg Seidel
Soichi Kodama
Seiko Shirane
Takafumi Ichida
Shigeru Makino
Makoto Yoshino
Jong Hon Kang
Masashi Mizuguchi
Bruce A. Barshop
Shohei Fuchinoue
Sara Seneca
Susan Zeesman
Ina Knerr
Margarita Rodés
Pornswan Wasant
Ichiro Yoshida
Linda De Meirleir
Abdul Md Jalil
Laila Begum
Masahisa Horiuchi
Nobuhiko Katunuma
Shiro Nakagawa
Takeyori Saheki
Kagoshima University
Tokushima Bunri University
Hacettepe University, Faculty of Medicine
Universitat Tubingen
University of Innsbruck
Rambam Health Care Campus Israel
Friedrich Schiller Universitat Jena
Himeji Red Cross Hospital
Niigata National Hospital
Niigata University School of Medicine
Uji Tokushukai Hospital
Kurume University School of Medicine
Teine Keijinkai Hospital
Jichi Medical University
University of California, San Diego, School of Medicine
Tokyo Women's Medical University
Universitair Ziekenhuis Brussel
Department of Pediatrics
Friedrich-Alexander-Universität Erlangen-Nürnberg
Institut de Bioquimica Clinica, Barcelona
Mahidol University
Vrije Universiteit Brussel
Keywords: Biochemistry, Genetics and Molecular Biology
Issue Date: 16-Jul-2003
Citation: Human Mutation. Vol.22, No.1 (2003), 24-34
Abstract: Classical citrullinemia (CTLN1), a rare autosomal recessive disorder, is caused by mutations of the argininosuccinate synthetase (ASS) gene, localized on chromosome 9q34.1. ASS functions as a rate-limiting enzyme in the urea cycle. Previously, we identified 32 mutations in the ASS gene of CTLN1 patients mainly in Japan and the United States, and to date 34 different mutations have been described in 50 families worldwide. In the present study, we report ASS mutations detected in 35 additional CTLN1 families from 11 countries. By analyzing the entire coding sequence and the intron-exon boundaries of the ASS gene using RT-PCR and/or genomic DNA-PCR, we have identified 16 novel mutations (two different 1-bp deletions, a 67-bp insertion, and 13 missense) and have detected 12 known mutations. Altogether, 50 different mutations (seven deletion, three splice site, one duplication, two nonsense, and 37 missense) in 85 CTLN1 families were identified. On the basis of primary sequence comparisons with the crystal structure of E. coli ASS protein, it may be concluded that any of the 37 missense mutations found at 30 different positions led to structural and functional impairments of the human ASS protein. It has been found that three mutations are particularly frequent: IVS6-2A>G in 23 families (Japan: 20 and Korea: three), G390R in 18 families (Turkey: six, U.S.: five, Spain: three, Israel: one, Austria: one, Canada: one, and Bolivia: one), and R304W in 10 families (Japan: nine and Turkey: one). Most mutations of the ASS gene are "private" and are distributed throughout the gene, except for exons 5 and 12-14. It seems that the clinical course of the patients with truncated mutations or the G390R mutation is early,onset/severe. The phenotype of the patients with certain missense mutations (G362V or W179R) is more late-onset/mild. Eight patients with R86H, A118T, R265H, or K310R mutations were adult/late-onset and four of them showed severe symptoms during pregnancy or postpartum. However, it is still difficult to prove the genotype-phenotype correlation, because many patients were compound heterozygotes (with two different mutations), lived in different environments at the time of diagnosis, and/or had several treatment regimes or various knowledge of the disease. © 2003 Wiley-Liss, Inc.
ISSN: 10597794
Appears in Collections:Scopus 2001-2005

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