The Significance Of SLC25A13 Gene Mutation In Chinese Infants With Intrahepatic Cholestasis

In 2001,SLC25A13 gene mutations were found in Japanese neonatal abnormal metabolism screening intrahepatic cholestasis children,and thus Neonatal Intrahepatic Cholestasis caused by Citrin Deficiency(NICCD) was named.The clinical manifestation of NICCD was diverse with distinctive blood amino acids upgrading in most children.Early studies regarded NICCD as self-limited disease,however,later studies found that some children may died of severe hypoproteinemia and blood clotting disfunction in neonatal period.Some NICCD patients may developed to severe Adult-onset typeⅡcitrullinemia(CTLN2) after symptoms disappearing some years or some decade years.It leaded to liver function damage and hepatic failure ulimately needing liver transplatation,and some may developed to sudden death.So the early diagnosis of NICCD is very important for treatment guidance and prognosis.Recent years,with the development of SLC25A13 gene study,the carrier rate was found to be high in many countries,such as Japan.China.Korea,besides new mutations were detected out constantly. The mutation form and frequence differ greatly in different countries.Individual cases of SLC25A13 gene mutation had been reported in Chinese infantile intrahepatic cholestasis.Datas have revealed that the carrier rate of Chinese healthly people is 1/65,speculating SLC25A13 gene mutations were not rare in Chinese people.Due to the difference of gene mutations in race and district,it's necessary to approach the feature of Chinese people SLC25A13 gene mutations.So,SLC25A13 gene mutations were analyzed in our infantile intrahepatic cholestasis patients to know the mutational spectrum feature and incidence.Section 1 SLC25A13 gene mutation in Chinese infants with intrahepatic cholestasis and abnormal blood amino acidsObjectives:To explore whether SLC25A13 gene mutation exists and its mutation spectrum in infants with intrahepatic cholestasis and abnormal blood amino acids from Mainland China.Methods:Blood amino acids were analyzed by mass chromatographic analysis in infants who were referred to Children's Hospital of Fudan University for investigation of intrahepatic cholestasis of unknown origin from 2003.6 to 2007.6.SLC25A13 gene mutations were detected in 14 children whose serum level of citrulline and/or methionine is at least two times the upper normal range.12 reported mutations were detected in all the selected objects first.In the patient in whom only one mutation was detected,all other exons and their neighboring sequences were analyzed afterwards.Results:SLC25A13 gene mutations were found in 8 patients,including 2 patients with compound heterozygous mutation 851de14/1638ins23,and homozygous mutation 851de14/851de14,compound heterozygous mutation 851de14/R184X and homozygous mutation IVS6+1G＞A/IVS6+1G＞A in one each, and heterozygous mutation 851de14 in 3 patients.Brief summary:SLC25A13 gene mutations exist in Chinese infants with intrahepatic cholestasis and abnormal blood amino acids.Their mutation spectrum is different from Japan.851de14 and 1638ins23 are common mutations in China,and especially 851de14 is the most common form. Mutation IVS11+1G＞A has not been found.Mutation IVS6+1G＞A has not been reported before. Section 2 The incidence of SLC25A13 Gene Mutations in Infantile Intrahepatic Cholestasis patientsObjectives:To explore the prevalence of SLC25A13 gene mutations in Chinese infants with intrahepatic cholestasis.Methods:Blood amino acids were analyzed by using mass chromatography in 115 infants who were referred to our hospital for further investigations of intrahepatic cholestasis from December 2003 to December 2006.All exons and their neighbouring sequences of SLC25A13 gene were analysed in 10 children whose serum level of citrulline and/or methionine is at least two times the upper normal range.In all,5 patients with SLC25A13 gene mutation were found.Two most common mutations of SLC25A13 gene,[Ⅰ]and [Ⅲ]were screened in children without citrulline and/or methionine elevation.Mutation[Ⅰ]was detected by real-time fluorescent quantitation PCR double labelling probes and mutation[Ⅲ]was detected by electrophoresis of PCR products.If the children in whom only one heterozygous mutation was found,all exons and nearby sequences were analysed then after.Results:5 cases of SLC25A13 gene mutation were also found in other 105 intrahepatic cholestasis patients,including 1 patient with homozygous mutation 851de14/851de14 and 4 patients with heterozygous mutation 851de14.Totally,SLC25A13 gene mutations were detected in 10 of the 115 intrahepatic cholestasis patients.Therefore,the incidence is 8.7%. Brief summary:SLC25A13 gene mutation is one of the important causes of Chinese infantile intrahepatic cholestasis.The real-time PCR method is accurate and trustworthy for detecting SLC25A13 gene mutation 851de14.Conclusions:SLC25A13 gene mutations exist in Chinese infants with intrahepatic cholestasis and abnormal blood amino acids.Their mutation spectrum is different from Japan.851de14 and 1638ins23 are common mutations in China,and especially 851de14 is the most common form. Mutation IVS11+IG＞A has not been found.Mutation IVS6+IG＞A has not been reported before.SLC25A13 gene mutation is one of the important causes of Chinese infantile intrahepatic cholestasis.The real-time PCR method is accurate and trustworthy for detecting SLC25A13 gene mutation 851de14.