Screening for Five Prevalent Mutations of &lt;i&gt;SLC25A13&lt;/i&gt; Gene in Guangdong, China: A Molecular Epidemiologic Survey of Citrin Deficiency

Zhang, Zhan Hui; Yang, Zhi; Chen, Feng Ping; Kikuchi, Atsuo; Liu, Zhen Huan; Kuang, Li Zhen; Li, Wei Ming; Shi, Yuan; Kure, Shigeo; Saheki, Takeyori

doi:10.1620/tjem.233.275

Cited by 9 publications

(9 citation statements)

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“…Although about 200 Chinese NICCD patients have been diagnosed via SLC25A13 analysis to date 22 25 26 27 , this number was rather limited, since China might have 85700 CD patients according to provisional epidemiological data 19 27 28 . Moreover, the SLC25A13 mutations worldwide demonstrate remarkable heterogeneity 12 22 23 24 27 29 30 31 32 33 34 35 36 37 38 . China is a vast country with a huge population, but the SLC25A13 genotypic features of CD patients, including the mutation spectrum and their geographic distribution, remains far from being well clarified in our country.…”

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confidence: 99%

Molecular diagnosis of pediatric patients with citrin deficiency in China: SLC25A13 mutation spectrum and the geographic distribution

Lin

Zeng

Zhang

et al. 2016

Sci Rep

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Citrin deficiency (CD) is a Mendelian disease due to biallelic mutations of SLC25A13 gene. Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) is the major pediatric CD phenotype, and its definite diagnosis relies on SLC25A13 genetic analysis. China is a vast country with a huge population, but the SLC25A13 genotypic features of CD patients in our country remains far from being well clarified. Via sophisticated molecular analysis, this study diagnosed 154 new CD patients in mainland China and identified 9 novel deleterious SLC25A13 mutations, i.e. c.103A > G, [c.329 − 154_c.468 + 2352del2646; c.468 + 2392_c.468 + 2393ins23], c.493C > T, c.755 − 1G > C, c.845_c.848 + 1delG, c.933_c.933 + 1insGCAG, c.1381G > T, c.1452 + 1G > A and c.1706_1707delTA. Among the 274 CD patients diagnosed by our group thus far, 41 SLC25A13 mutations/variations were detected. The 7 mutations c.775C > T, c.851_854del4, c.1078C > T, IVS11 + 1G > A, c.1364G > T, c.1399C > T and IVS16ins3kb demonstrated significantly different geographic distribution. Among the total 53 identified genotypes, only c.851_854del4/c.851_854del4 and c.851_854del4/c.1399C > T presented different geographic distribution. The northern population had a higher level of SLC25A13 allelic heterogeneity than those in the south. These findings enriched the SLC25A13 mutation spectrum and brought new insights into the geographic distribution of the variations and genotypes, providing reliable evidences for NICCD definite diagnosis and for the determination of relevant molecular targets in different Chinese areas.

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Molecular diagnosis of pediatric patients with citrin deficiency in China: SLC25A13 mutation spectrum and the geographic distribution

Lin

Zeng

Zhang

et al. 2016

Sci Rep

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“…A molecular survey on citrin deficiency epidemiology in Guangdong province, China, reported that the carrier rate of the four prevalent SLC25A13 mutations was ~2.06% (50/2,428), theoretically, with the number of citrin-deficiency patients >11,000 in this population ( 15 ). These survey samples were collected from different cities in Guangdong province, but did not include Jiangmen city.…”

Section: Discussionmentioning

confidence: 99%

“…The overall pathogenic variant carrier rate has been reported to be as high as 2% in southern China, which is the highest carrier frequency currently reported ( 13 , 15 ). A total of >11,000 individuals are estimated to be homozygous or compound heterozygous for SLC25A13 pathogenic variants in the Guangdong province in southern China ( 15 ). Currently, >80 SLC25A13 pathogenic variants have been identified, but among them, four prevalent mutations c.851_854del (p.R284fs286X), c.1638_1660dup (p.A554fs570X), IVS6+5G>A (p.A206fs212X), and IVS16ins3kb (p.A584fs585X) account for >80% of the Chinese population who exhibit citrin deficiency ( 16 – 18 ).…”

Section: Introductionmentioning

confidence: 97%

“…Citrin deficiency was first reported and described in Japan, but later was recognized to be a pan ethnic disease with high prevalence among the East Asian population (1,11,13,14). The overall pathogenic variant carrier rate has been reported to be as high as 2% in southern China, which is the highest carrier frequency currently reported (13,15). A total of >11,000 individuals are estimated to be homozygous or compound heterozygous for SLC25A13 pathogenic variants in the Guangdong province in southern China (15).…”

Section: Introductionmentioning

confidence: 99%

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Rapid Genetic Diagnosis of Citrin Deficiency by Multicolor Melting Curve Analysis

Zeng¹,

Yang²,

Luo³

et al. 2021

Front. Pediatr.

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Citrin deficiency caused by SLC25A13 genetic mutations is an autosomal recessive disease, and four prevalent mutations including c.851_854del, c.1638_1660dup, IVS6+5G>A, and IVS16ins3kb make up >80% of total pathogenic mutations within the Chinese population. However, suitable assays for detection of these mutations have not yet been developed for use in routine clinical practice. In the current study, a real-time PCR-based multicolor melting curve analysis (MMCA) was developed to detect the four prevalent mutations in one closed-tube reaction. The analytical and clinical performances were evaluated using artificial templates and clinical samples. All four mutations in the test samples were accurately genotyped via their labeling fluorophores and Tm values, and the standard deviations of Tm values were indicated to be <0.2°C. The limit of detection was estimated to be 500 diploid human genomes per reaction. The MMCA assay of 5,332 healthy newborns from southern China identified a total of 107 SLC25A13-mutation carriers, indicating a carrier rate of 2%. The genotypes of 107 carriers and 112 random non-carriers were validated using direct sequencing and Long-range PCR with 100% concordance. In conclusion, the assay developed in this study may potentially serve as a rapid genetic diagnostic tool for citrin deficiency.

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“…To date, a total of 106 pathogenic SLC25A13 mutations/variations have been reported [ 11 , 14 , 22 , 25 , 32 – 41 ], most of which are point mutations or short insertions/deletions. Among the SLC25A13 mutations detected in Chinese CD patients, c.851_854del, c.1638_1660dup, c.615+5G>A and IVS16ins3kb account for about 85% of all mutated alleles [ 11 , 25 , 36 ]. Nowadays, these four high-frequency mutations have been screened by conventional means of Polymerase Chain Reaction (PCR), Long and Accurate PCR (LA-PCR) and PCR-Restriction Fragment Length Polymorphism (PCR-RFLP) procedures, respectively, as the basic molecular targets for NICCD diagnosis.…”

Section: Introductionmentioning

confidence: 99%

Molecular diagnosis of citrin deficiency in an infant with intrahepatic cholestasis: identification of a 21.7kb gross deletion that completely silences the transcriptional and translational expression of the affected SLC25A13 allele

et al. 2017

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Neonatal Intrahepatic Cholestasis caused by Citrin Deficiency (NICCD) arises from biallelic SLC25A13 mutations, and SLC25A13 analysis provides reliable evidences for NICCD definite diagnosis. However, novel large insertions/deletions in this gene could not be detected just by conventional DNA analysis. This study aimed to explore definite diagnostic evidences for an infant highly-suspected to have NICCD. Prevalent mutation screening and Sanger sequencing of SLC25A13 gene just revealed a paternally-inherited mutation c.851_854del4. Nevertheless, neither citrin protein nor SLC25A13 transcripts of maternal origin could be detected on Western blotting and cDNA cloning analysis, respectively. On this basis, the hidden maternal mutation was precisely positioned using SNP analysis and semi-quantitative PCR, and finally identified as a novel large deletion c.-3251_c.15+18443del21709bp, which involved the SLC25A13 promoter region and the entire exon 1 where locates the translation initiation codon. Hence, NICCD was definitely diagnosed in the infant. To the best of our knowledge, the novel gross deletion, which silenced the transcriptional and translational expression of the affected SLC25A13 allele, is the hitherto largest deletion in SLC25A13 mutation spectrum. The Western blotting approach using mitochondrial protein extracted from expanded peripheral blood lymphocytes, of particular note, might be a new minimally-invasive and more-feasible molecular tool for NICCD diagnosis.

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Screening for Five Prevalent Mutations of <i>SLC25A13</i> Gene in Guangdong, China: A Molecular Epidemiologic Survey of Citrin Deficiency

Cited by 9 publications

References 28 publications

Molecular diagnosis of pediatric patients with citrin deficiency in China: SLC25A13 mutation spectrum and the geographic distribution

Molecular diagnosis of pediatric patients with citrin deficiency in China: SLC25A13 mutation spectrum and the geographic distribution

Rapid Genetic Diagnosis of Citrin Deficiency by Multicolor Melting Curve Analysis

Molecular diagnosis of citrin deficiency in an infant with intrahepatic cholestasis: identification of a 21.7kb gross deletion that completely silences the transcriptional and translational expression of the affected SLC25A13 allele

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