Frequency and distribution in East Asia of 12 mutations identified in the SLC25A13 gene of Japanese patients with citrin deficiency

Abstract

Deficiency of citrin, a liver-type mitochondrial aspartate-glutamate carrier (AGC), encoded by the SLC25A13 gene on chromosome 7q21.3, causes autosomal recessive disorders: adult-onset type II citrullinemia (CTLN2) and neonatal hepatitis associated with intrahepatic cholestasis (NICCD). So far, we have described 12 SLC25A13 mutations: 11 were from Japan and one from Israel. Three mutations found in Chinese and Vietnamese patients were the same as those in Japanese patients. In the present study, we identified a novel mutation IVS6+1G>C in a Japanese CTLN2 patient and widely screened 12 SLC25A13 mutations found in Japanese patients in control individuals from East Asia to confirm our preliminary results that the carrier frequency was high in Asian populations. Mutations 851-854del and 1638-1660dup were found in all Asian countries tested, and 851-854del associated with 290-haplotype in microsatellite marker D7S1812 was especially frequent. Other mutations frequently detected were IVS11+1G>A in Japanese and Korean, S225X in Japanese, and IVS6+5G>A in Chinese populations. We found a remarkable difference in carrier rates in China (including Taiwan) between north (1/ 940) and south (1/48) of the Yangtze River. We detected many carriers in Chinese (64/4169 = 1/65), Japanese (20/1372 = 1/69) and Korean (22/2455 = 1/112) populations, suggesting that over 80,000 East Asians are homozygotes with two mutated SLC25A13 alleles.

Mutational analysis of 65 Wilson disease patients in Hong Kong Chinese: Identification of 17 novel mutations and its genetic heterogeneity

“…Studies on disease genes, such as phenylalanine hydroxylase (PAH) for phenylketonuria (Lo et al 1993;Wang et al 1991) and citrin (SLC25A13) for adult-onset type II citrillinemia (Lu et al 2005), were consistent with the findings of Zhao and Lee. A founder mutation of classical hyperphenylalanemia, p.R413P, was mostly present in Chinese populations north of the Yangtze River (Wang et al 1991), while a common mutation of SLC25A13, c.851_854del, only occurred in Chinese populations south of the Yangtze River (Lu et al 2005). A complete description of early populations must allow, therefore, the possibility of admixture of Chinese populations across the Yangtze River.…”

Citrin deficiency as a cause of chronic liver disorder mimicking non-alcoholic fatty liver disease

“…Sixteen SLC25A13 mutations found relatively frequently in Japan, 13 mutations described previously [4,6,[23][24][25] and three unpublished novel mutations (Tabata et al, manuscript in preparation), were tested by the polymerase chain reaction-restriction fragment length polymorphism method and/or multiple methods using Genescan/SNaPshot. A novel mutation identified by PCR/sequencing of all 18 exons and the flanking sequences in an allele of a CTLN2 patient (No.…”

“…Some of the mutations identified in Japanese patients are frequently found in the East Asian population, and the prevalence of these mutations has been estimated to be 1/65 in China, 1/112 in Korea, and 1/69 in Japan [3,5,6]. Furthermore, several cases with SLC25A13 gene mutations have been reported in Israel, USA, and elsewhere [7][8][9], indicating a world-wide incidence of citrin deficiency.…”

Six cases of citrin deficiency in Korea

“…- (5,20). These results suggest that the incidence of citrin deficiency is 1/50,000 in Korea and 1/19,000 in Japan.…”