title: Identification of 13 novel mutations including a retrotransposal insertion in SLC25A13 gene and frequency of 30 mutations found in patients with citrin deficiency.
abstract: Deficiency of citrin, liver-type mitochondrial aspartate-glutamate carrier, is an autosomal recessive disorder caused by mutations of the SLC25A13 gene on chromosome 7q21.3 and has two phenotypes: neonatal intrahepatic cholestatic hepatitis (NICCD) and adult-onset type II citrullinemia (CTLN2). So far, we have described 19 SLC25A13 mutations. Here, we report 13 novel SLC25A13 mutations (one insertion, two deletion, three splice site, two nonsense, and five missense) in patients with citrin deficiency from Japan, Israel, UK, and Czech Republic. Only R360X was detected in both Japanese and Caucasian. IVS16ins3kb identified in a Japanese CTLN2 family seems to be a retrotransposal insertion, as the inserted sequence (2,667-nt) showed an antisense strand of processed complementary DNA (cDNA) from a gene on chromosome 6 (C6orf68), and the repetitive sequence (17-nt) derived from SLC25A13 was found at both ends of the insert. All together, 30 different mutations found in 334 Japanese, 47 Chinese, 11 Korean, four Vietnamese and seven non-East Asian families have been summarized. In Japan, IVS16ins3kb was relatively frequent in 22 families, in addition to known mutations IVS11 + 1G > A, 851del4, IVS13 + 1G > A, and S225X in 189, 173, 48 and 30 families, respectively; 851del4 and IVS16ins3kb were found in all East Asian patients tested, suggesting that these mutations may have occurred very early in some area of East Asia.
authors.affiliation: Department of Molecular Metabolism and Biochemical Genetics, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Tabata
authors.affiliation: Department of Molecular Metabolism and Biochemical Genetics, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.
authors.forename: Jian-Sheng
authors.initials: JS
authors.lastname: Sheng
authors.affiliation: Department of Molecular Metabolism and Biochemical Genetics, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.
authors.forename: Miharu
authors.initials: M
authors.lastname: Ushikai
authors.affiliation: Department of Molecular Metabolism and Biochemical Genetics, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.|Department of Pediatrics, First Affiliated Hospital, Jinan University, Guangzhou, 510632, China.
authors.forename: Yuan-Zong
authors.initials: YZ
authors.lastname: Song
authors.affiliation: Department of Molecular Metabolism and Biochemical Genetics, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.|Department of Brain Surgery, The Second Clinical College of Fujian Medical University, Quanzhou, 362000, China.
authors.forename: Hong-Zhi
authors.initials: HZ
authors.lastname: Gao
authors.affiliation: Department of Molecular Metabolism and Biochemical Genetics, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.|Department of Biochemistry, Pharmacy College, Hunan University of Traditional Chinese Medicine, Changsha, 410007, China.
authors.forename: Yao-Bang
authors.initials: YB
authors.lastname: Lu
authors.affiliation: Department of Molecular Metabolism and Biochemical Genetics, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Okumura
authors.affiliation: Department of Molecular Metabolism and Biochemical Genetics, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.
authors.forename: Mikio
authors.initials: M
authors.lastname: Iijima
authors.affiliation: Department of Pediatrics, Shimada Municipal Hospital, Shizuoka, 427-8502, Japan.
authors.forename: Kozo
authors.initials: K
authors.lastname: Mutoh
authors.affiliation: Department of Molecular Metabolism and Biochemical Genetics, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.
authors.forename: Shosei
authors.initials: S
authors.lastname: Kishida
authors.affiliation: Department of Molecular Metabolism and Biochemical Genetics, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.|Institute for Health Sciences, Tokushima Bunri University, Tokushima, 770-8514, Japan.
authors.forename: Takeyori
authors.initials: T
authors.lastname: Saheki
authors.affiliation: Department of Molecular Metabolism and Biochemical Genetics, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan. dodoko12@m.kufm.kagoshima-u.ac.jp.
authors.forename: Keiko
authors.initials: K
authors.lastname: Kobayashi
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D002780:Cholestasis, Intrahepatic / Q000235:genetics; D020159:Citrullinemia / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D006505:Hepatitis / Q000235:genetics; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D026901:Membrane Transport Proteins / Q000172:deficiency* / Q000235:genetics*; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins / Q000172:deficiency* / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D018626:Retroelements; D017386:Sequence Homology, Amino Acid
chemical_list: D017931:DNA Primers; D018076:DNA, Complementary; D026901:Membrane Transport Proteins; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins; D018626:Retroelements; C119629:SLC25A13 protein, human