SLC25A13 gene analysis in citrin deficiency: sixteen novel mutations in East Asian patients, and the mutation distribution in a large pediatric cohort in China.
BACKGROUND
The human SLC25A13 gene encodes citrin, the liver-type mitochondrial aspartate/glutamate carrier isoform 2 (AGC2), and SLC25A13 mutations cause citrin deficiency (CD), a disease entity that encompasses different age-dependant clinical phenotypes such as Adult-onset Citrullinemia Type II (CTLN2) and Neonatal Intrahepatic Cholestasis caused by Citrin Deficiency (NICCD). The analyses of SLC25A13 gene and its protein/mRNA products remain reliable tools for the definitive diagnoses of CD patients, and so far, the SLC25A13 mutation spectrum in Chinese CD patients has not been well-characterized yet.


RESULTS
By means of direct DNA sequencing, cDNA cloning and SNP analyses, 16 novel pathogenic mutations, including 9 missense, 4 nonsense, 1 splice-site, 1 deletion and 1 large transposal insertion IVS4ins6kb (GenBank accession number KF425758), were identified in CTLN2 or NICCD patients from China, Japan and Malaysia, respectively, making the SLC25A13 variations worldwide reach the total number of 81. A large NICCD cohort of 116 Chinese cases was also established, and the 4 high-frequency mutations contributed a much larger proportion of the mutated alleles in the patients from south China than in those from the north (χ(2) = 14.93, P<0.01), with the latitude of 30°N as the geographic dividing line in mainland China.


CONCLUSIONS
This paper further enriched the SLC25A13 variation spectrum worldwide, and formed a substantial contribution to the in-depth understanding of the genotypic feature of Chinese CD patients.
Department of Pediatrics, The First Affiliated Hospital, Jinan University, Guangzhou, China.
Yuan-Zong
YZ
Song
Zhan-Hui
ZH
Zhang
Wei-Xia
WX
Lin
Xin-Jing
XJ
Zhao
Mei
M
Deng
Yan-Li
YL
Ma
Li
L
Guo
Feng-Ping
FP
Chen
Xiao-Ling
XL
Long
Xiang-Ling
XL
He
Yoshihide
Y
Sunada
Shun
S
Soneda
Akiko
A
Nakatomi
Sumito
S
Dateki
Lock-Hock
LH
Ngu
Keiko
K
Kobayashi
Takeyori
T
Saheki
D000595:Amino Acid Sequence; D044466:Asian People / Q000235:genetics*; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D002681:China; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D004251:DNA Transposable Elements; D018076:DNA, Complementary / Q000737:chemistry / Q000235:genetics; D005260:Female; D023061:Gene Order; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D033681:Mitochondrial Membrane Transport Proteins / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics*; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D009154:Mutation; D016415:Sequence Alignment
D004251:DNA Transposable Elements; D018076:DNA, Complementary; D033681:Mitochondrial Membrane Transport Proteins; C119629:SLC25A13 protein, human