Publication:
Identification of 16 novel mutations in the argininosuccinate synthetase gene and genotype-phenotype correlation in 38 classical citrullinemia patients

3

Issued Date

2003-07-16

Resource Type

Article

ISSN

10597794

DOI

10.1002/humu.10230

Other identifier(s)

2-s2.0-0038385026

Rights

Mahidol University

Rights Holder(s)

SCOPUS

Bibliographic Citation

Human Mutation. Vol.22, No.1 (2003), 24-34

Suggested Citation

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 Identification of 16 novel mutations in the argininosuccinate synthetase gene and genotype-phenotype correlation in 38 classical citrullinemia patients. Human Mutation. Vol.22, No.1 (2003), 24-34. doi:10.1002/humu.10230 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/20709

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Title

Identification of 16 novel mutations in the argininosuccinate synthetase gene and genotype-phenotype correlation in 38 classical citrullinemia patients

Author(s)

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

Other Contributor(s)

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

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.

Keyword(s)

Biochemistry, Genetics and Molecular Biology

Availability

URI

https://repository.li.mahidol.ac.th/handle/123456789/20709

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Scopus 2001-2005