The gene mutated in adult-onset type II citrullinaemia encodes a putative mitochondrial carrier protein

Kobayashi, Keiko; Sinasac, David S.; Iijima, Mikio; Boright, Andrew P.; Begum, Laila; Lee, Jeffrey R.; Yasuda, Tomotsugu; Ikeda, Sayaka; Hirano, Ryuki; Terazono, Hiroki; Crackower, Michael A.; Kondo, Ikuko; Tsui, Lap‐Chee; Scherer, Stephen W.; Saheki, Takeyori

doi:10.1038/9667

Cited by 375 publications

(379 citation statements)

References 25 publications

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“…aa, amino acids; EF, calcium-binding EF hand motif; TM, mitochondrial (mit) transmembrane spanner; IM, inner membrane. The figure is based on data reported by Kobayashi et al (1999), Sinasac et al (1999), Yasuda et al (2000), and Yamaguchi et al (2002) Yasuda et al 2000;Yamaguchi et al 2002) CTLN2, adult-onset type II citrullinemia; NICCD, neonatal intrahepatic cholestasis caused by citrin deficiency * CTLN2/control and NICCD/control (P Ͻ 0.01) a ratio to mutated alleles b ratio to total alleles c Four novel mutations identified will be published elsewhere …”

Section: Neonatal Intrahepatic Cholestasis Caused By Citrin Deficiencmentioning

confidence: 99%

Mitochondrial aspartate glutamate carrier (citrin) deficiency as the cause of adult-onset type II citrullinemia (CTLN2) and idiopathic neonatal hepatitis (NICCD)

2002

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Mitochondrial aspartate glutamate carrier (citrin) deficiency as the cause of adult-onset type II citrullinemia (CTLN2) and idiopathic neonatal hepatitis (NICCD) Abstract By using homozygosity mapping and positional cloning, we have shown that adult-onset type II citrullinemia (CTLN2) is caused by mutations of the SLC25A13 gene, which is localized on chromosome 7q21.3 and encodes a mitochondrial solute carrier protein named citrin. So far, we have reported nine mutations, most of which cause loss of citrin, and we have established several methods for DNA diagnosis. These methods have shown that more than 90% of the patients diagnosed as suffering from CTLN2 by enzymatic analysis carry SLC25A13 mutations in both alleles, indicating that CTLN2 is caused by citrin deficiency. Furthermore, by using the same DNA diagnosis methods, we discovered that 70 neonates or infants suffering from a particular type of neonatal hepatitis carry the same SLC25A13 mutations. Since the symptoms of the neonates are different from those of the more severe CTLN2 and usually ameliorate without special treatment, we designated the neonatal disease neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). We conclude that citrin deficiency causes NICCD in neonates and CTLN2 in adults through the additional effects of genetic or environmental modifiers. Since the function of citrin, together with that of an isoform, aralar, was found to be as a mitochondrial aspartate glutamate carrier, the various symptoms of NICCD and CTLN2 may be understood as caused by defective aspartate export from the mitochondria to the cytosol and defects in the malate aspartate shuttle. It is, however, still difficult to understand the cause of the hepatic deficiency of argininosuccinate synthetase protein in CTLN2.Received

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Section: Neonatal Intrahepatic Cholestasis Caused By Citrin Deficiencmentioning

confidence: 99%

Mitochondrial aspartate glutamate carrier (citrin) deficiency as the cause of adult-onset type II citrullinemia (CTLN2) and idiopathic neonatal hepatitis (NICCD)

2002

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“…With this in mind, we focused on citrin deficiency (Kobayashi et al 1999) and pyridoxine-dependent autism (Kuriyama et al 2002), a subgroup of autism expected to benefit from pyridoxine treatment, which shows similar clinical features to pyridoxinedependent epilepsy but without seizures. The findings of specific symptoms of these diseases will be reported in separate publications.…”

Section: Target Diseases and Questionnaire Itemsmentioning

confidence: 99%

Protocol and Research Perspectives of the ToMMo Child Health Study after the 2011 Great East Japan Earthquake

Kikuya

Miyashita

Yamanaka

et al. 2015

Tohoku J. Exp. Med.

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Residents of areas affected by the Great East Japan Earthquake may suffer from diseases or health problems. We are conducting a cross-sectional study from 2012 to 2015 to investigate and address the health needs of schoolchildren affected by this disaster. In this paper, we describe the protocol and research perspectives of our long-term child health study, and present the results obtained immediately after the disaster. The parent-administered questionnaire includes the International Study of Asthma and Allergies in Childhood questionnaire for asthma and eczema symptoms, the Strengths and Difficulties Questionnaire (SDQ), and a questionnaire on influenza infection and vaccination status. In 2012, we distributed the questionnaire to 3,505 (2 nd , 4 th , 6 th , and 8 th graders) in three municipalities located in southern coastal area among the 28 municipalities, and 1,277 (36.4%) returned the completed questionnaire. Mean age was 11.1 ± 2.2 years old. The number of children with symptoms of wheeze and eczema in the past 12 months was 146 (11.4%) and 199 (15.6%), respectively. The SDQ total difficulties score revealed 174 (13.6%) children with some form of difficulty in their daily lives. From May 2011 to April 2012, 195 (15.3%) and 649 (50.8%) children received the influenza vaccination once and twice, respectively, and 532 (41.7%) had suffered from influenza. The prevalence of eczema symptoms or some form of difficulty was higher than the Japanese average. However, careful interpretation was required because of potential self-selection bias from the low response rate. We will continue this study of schoolchildren to provide aggregate findings.

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“…From this, the former type II citrullinemia (MIM] 603471) can be distinguished: Kobayashi et al [1999] revealed genetic aberrations in the SLC25A13 gene, coding for citrin, a glutamate-aspartate transporter located in the mitochondrial membrane, as the underlying cause of this disease. In some patients with citrin deficiency neonatal or childhood onset is observed but most manifestations occur during adult life.…”

Section: Introductionmentioning

confidence: 99%

Mutations and polymorphisms in the human argininosuccinate synthetase (ASS1) gene

2008

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Citrullinemia type I is an autosomal recessive disorder that is caused by a deficiency of the urea cycle enzyme argininosuccinate synthetase (ASS1). Deficiency of ASS1 shows various clinical manifestations encompassing severely affected patients with fatal neonatal hyperammonemia as well as asymptomatic individuals with only a biochemical phenotype. This is a comprehensive report of all 87 mutations found to date in the ASS1 gene on chromosome 9q34.1. A large proportion of the mutations (n 5 27) are described here for the first time. Mutations are distributed throughout exons 3 to 15, most of them being identified in exons 5, 12, 13, and 14. The mutation G390R in exon 15 is the single most common mutation in patients with the classical phenotype. Certain mutations clearly link to specific clinical courses but the clinical phenotype cannot be anticipated in all patients. This update presents a survey of the correlation between mutations in the ASS1 gene and the respective clinical courses as described so far. It also sheds light on the geographic incidence of the mutations. Enzymatic studies have been done in bacterial and human cell systems. However, the prognostic value of genetic aberrations with respect to their effect on protein function and clinical manifestation remains uncertain.

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The gene mutated in adult-onset type II citrullinaemia encodes a putative mitochondrial carrier protein

Cited by 375 publications

References 25 publications

Mitochondrial aspartate glutamate carrier (citrin) deficiency as the cause of adult-onset type II citrullinemia (CTLN2) and idiopathic neonatal hepatitis (NICCD)

Mitochondrial aspartate glutamate carrier (citrin) deficiency as the cause of adult-onset type II citrullinemia (CTLN2) and idiopathic neonatal hepatitis (NICCD)

Protocol and Research Perspectives of the ToMMo Child Health Study after the 2011 Great East Japan Earthquake

Mutations and polymorphisms in the human argininosuccinate synthetase (ASS1) gene

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