1.Phenylalanine Hydroxylase Deficiency and Citrin Deficiency in a Chinese Infant.
Jun YE ; Wen-Juan QIU ; Lian-Shu HAN ; Hui-Wen ZHANG ; Xue-Fan GU
Chinese Medical Journal 2015;128(21):2979-2980
2.Neonatal Intrahepatic Cholestasis Caused by Citrin Deficiency in Korean Infants.
Jae Sung KO ; Jung Han SONG ; Sung Sup PARK ; Jeong Kee SEO
Journal of Korean Medical Science 2007;22(6):952-956
Citrin is a liver-type mitochondrial aspartate-glutamate carrier encoded by the SLC25A13 gene, and its deficiency causes adult-onset type II citrullinemia and neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). Here, the authors investigated clinical findings in Korean infants with NICCD and performed mutation analysis on the SLC25A13 gene. Of 47 patients with neonatal cholestasis, three infants had multiple aminoacidemia (involving citrulline, methionine, and arginine) and galactosemia, and thus were diagnosed as having NICCD. Two of these three showed failure to thrive. The laboratory findings showed hypoproteinemia and hyperammonemia, and liver biopsies revealed micro-macrovesicular fatty liver and cholestasis. The three patients each harbored compound heterozygous 1,638-1,660 dup/ S225X mutation, compound heterozygous 851del4/S225X mutation, and heterozygous 1,638-1,660 dup mutation, respectively. With nutritional manipulation, liver functions were normalized and catch-up growth was achieved. NICCD should be considered in the differential diagnosis of cholestatic jaundice in Korean infants.
Amino Acids/blood
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Calcium-Binding Proteins/*deficiency
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Cholestasis, Intrahepatic/*etiology/genetics
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Citrullinemia/genetics
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Humans
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Infant
;
Membrane Transport Proteins/genetics
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Mitochondrial Proteins/genetics
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Mutation
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Organic Anion Transporters/*deficiency
3.A difficult and complicated case study: neonatal intrahepatic cholestasis caused by citrin deficiency.
Yuan-Zong SONG ; Hu HAO ; Miharu USHIKAI ; Guo-Sheng LIU ; Xin XIAO ; Takeyori SAHEKI ; Keiko KOBAYASHI ; Zi-Neng WANG
Chinese Journal of Contemporary Pediatrics 2006;8(2):125-128
Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) is a kind of inborn errors of metabolism, with the main clinic manifestations of jaundice, hepatomegaly, and abnormal liver function indices. As a mitochondrial solute carrier protein, citrin plays important roles in aerobic glycolysis, gluconeogenesis, urea cycle, and protein and nucleotide syntheses. Therefore citrin deficiency causes various and complicated metabolic disturbances, such as hypoglycemia, hyperlactic acidemia, hyperammonemia, hypoproteinemia, hyperlipidemia, and galactosemia. This paper reported a case of NICCD confirmed by mutation analysis of SLC25A13, the gene encoding citrin. The baby (male, 6 months old) was referred to the First Affiliated Hospital with the complaint of jaundice of the skin and sclera, which it had suffered from for nearly 6 months. Physical examination showed obvious jaundice and a palpable liver 5 cm below the right subcostal margin. Liver function tests revealed elevated enzymatic activities, like GGT, ALP, AST, and ALT, together with increased levels of TBA, bilirubin (especially conjugated bilirubin), and decreased levels of total protein/albumin and fibrinogen. Blood levels of ammonia, lactate, cholesterol, and triglyceride were also increased, and in particular, the serum AFP level reached 319,225.70 microg/L, a extremely elevated value that has rarely been found in practice before. Tandem mass analysis of a dried blood sample revealed increased levels of free fatty acids and tyrosine, methionine, citrulline, and threonine as well. UP-GC-MS analysis of the urine sample showed elevated galactose and galactitol. The baby was thus diagnosed with suspected NICCD based on the findings. It was then treated with oral arginine and multiple vitamins (including fat-soluble vitamins A, D, E, and K), and was fed with lactose-free and medium-chain fatty acids enriched formula instead of breast feeding. After half a month of treatment, the jaundice disappeared, and the laboratory findings, including liver function indices, blood levels of ammonia, lactate and AFP, were returned to normal level. The baby was followed up for 6 months. It developed well, and the abnormal laboratory findings, including MS-MS and UP-GC-MS analysis results, have been corrected, except a slightly elevated lactate level sometimes. SLC25A13 gene mutation analysis for the patient revealed a compound heterozygote of mutation 851del4 and 1638ins23 and therefore NICCD was definitely diagnosed.
Calcium-Binding Proteins
;
deficiency
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Cholestasis, Intrahepatic
;
diagnosis
;
etiology
;
therapy
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Humans
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Infant
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Male
;
Metabolism, Inborn Errors
;
diagnosis
;
etiology
;
therapy
;
Organic Anion Transporters
;
deficiency
4.Progresses and perspectives in the study on citrin deficiency.
Yao-bang LU ; Fei PENG ; Meng-xian LI ; Keiko KOBAYASHI ; Takeyori SAHEKI
Chinese Journal of Medical Genetics 2006;23(6):655-658
Citrin deficiency causes autosomal recessive disorders including adult-onset type II citrullinemia (CTLN2) and neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). The responsive gene of citrin deficiency, SLC25A13, locates on chromosome 7q21.3 and encodes citrin as a liver-type mitochondrial aspartate/glutamate carrier (AGC). The mutations on SLC25A13 will result in deficiency of citrin and CTLN2 or NICCD. Citrin deficiency was found at first in Japan. However, recently, some of cases were identified in China, Korea, Vietnam, Israel, Czech, United States and England, and racial differences of the SLC25A13 mutations were found, suggesting the patients with citrin deficiency maybe exist worldwide. In this article, authors reviewed the progresses in the study on citrin deficiency up to now and put forward authors' considerations for further research on it.
Animals
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Calcium-Binding Proteins
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deficiency
;
genetics
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Cholestasis, Intrahepatic
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genetics
;
surgery
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Chromosomes, Human, Pair 7
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Citrullinemia
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etiology
;
genetics
;
surgery
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Humans
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Liver Transplantation
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Membrane Transport Proteins
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genetics
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Mitochondrial Membrane Transport Proteins
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Mitochondrial Proteins
;
genetics
;
Organic Anion Transporters
;
deficiency
;
genetics
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Point Mutation
5.Analysis of SLC25A13 gene variants in 16 infants with intrahepatic cholestasis caused by citrin protein deficiency.
Wenwen LIU ; Xin MA ; Meijuan WANG ; Huijuan NING ; Xuemei ZHONG
Chinese Journal of Medical Genetics 2022;39(2):139-142
OBJECTIVE:
To explore the characteristics of SLC25A13 gene variants in 16 infants with neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD).
METHODS:
The infants were subjected to high-throughput DNA sequencing for coding exons and flanking regions of the target genes. Suspected variants were verified by Sanger sequencing and bioinformatic analysis.
RESULTS:
Among the 16 NICCD cases, 15 were found to harbor pathogenic variants. Among these, IVS14-9A>G, c.1640G>A, c.762T>A, c.736delG, c.1098Tdel and c.851G>A were previously unreported.
CONCLUSION
Six novel SLC25A13 variants were found by high-throughput sequencing, which has enriched the spectrum of SLC25A13 gene variants and provided a basis for genetic counseling and prenatal diagnosis.
Calcium-Binding Proteins/genetics*
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Cholestasis, Intrahepatic/genetics*
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Citrullinemia/genetics*
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Humans
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Infant
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Infant, Newborn
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Mitochondrial Membrane Transport Proteins/genetics*
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Mutation
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Organic Anion Transporters/genetics*
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Protein Deficiency
6.Utilization of high-resolution melting analysis to screen patients with neonatal intrahepatic cholestasis caused by citrin deficiency.
Peng-qiang WEN ; Guo-bing WANG ; Zhan-ling CHEN ; Dong CUI ; Xiao-hong LIU ; Li-fang YING ; Ping SONG ; Quan YUAN ; Shu-li CHEN ; Jian-xiang LIAO
Chinese Journal of Medical Genetics 2012;29(2):167-171
OBJECTIVETo assess the feasibility of high-resolution melting (HRM) analysis for screening patients with neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD).
METHODSBased on previous studies on SLC25A13 gene in Chinese patients with NICCD, four hotspot mutations (851del4, 1638ins23, IVS6+5G>A and IVS16ins3kb) were selected. Results of the HRM analysis was validated using 50 negative controls and 20 patients with NICCD whose genotypes were confirmed previously by direct sequencing. With the established protocol, 171 suspected patients were enrolled. Samples with abnormal melting curves were further validated by DNA sequencing.
RESULTSHRM analysis can accurately determine the genotypes of all negative controls and patients. The sensitivity and specificity of the technique reached 100% (70/70). The melting curves of samples with the same genotype were highly reproducible. In 171 suspected patients, seven NICCD patients were detected by HRM. Identified mutations have included one case of 851del4 homozygote, one case of IVS6+5G>A heterozygote, 3 cases of 851del4 heterozygotes, one case of [IVS6+5G>A]+[ 851del4] and one case of [1638ins23+IVS16ins3kb]+[1638ins23]. All mutations were subsequently confirmed by DNA sequencing.
CONCLUSIONHRM analysis is a convenient, high-throughput and rapid technique for the screening of NICCD patients.
Anion Transport Proteins ; genetics ; Base Sequence ; Calcium-Binding Proteins ; deficiency ; China ; Citrullinemia ; diagnosis ; genetics ; metabolism ; DNA ; chemistry ; genetics ; Genetic Predisposition to Disease ; Genotype ; Humans ; Mitochondrial Proteins ; genetics ; Molecular Sequence Data ; Mutation ; Nucleic Acid Denaturation ; Organic Anion Transporters ; deficiency ; Sensitivity and Specificity
7.Cloning and sequence analysis of SLC25A13 transcripts in human amniocytes.
Zhan-Hui ZHANG ; Xin-Jing ZHAO ; Yuan-Zong SONG ; Xiao-Mei TANG ; Qing-Bing ZHA
Chinese Journal of Contemporary Pediatrics 2012;14(3):221-225
OBJECTIVEThis research intends to amplify the entire coding region sequences of SLC25A13 mRNA which encodes citrin, and to investigate sequence features of the transcripts for this gene in cultured human amniocytes. This study will provide laboratory evidence for prenatal diagnosis of neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) at mRNA level.
METHODSOne amniocyte sample was collected from a pregnant woman who underwent prenatal diagnosis of citrin deficiency and whose fetus has proven a carrier of 851del4 mutation by genomic DNA analysis. Another amniocyte sample, as a control, was from a fetus without family history of citrin deficiency. Total RNA was extracted from cultured amniocytes, cDNA was synthesized, and then nested-PCR was performed to amplify the entire coding region sequences of SLC25A13. The PCR products were cloned and analyzed by sequencing.
RESULTSThe entire coding region of SLC25A13 gene was successful amplified from two cultured human amniocytes. The splice variant of SLC25A13, SLCA (normal mRNA), was identified in the two samples. SLCB (CAG insertion between exon 9-10) was identified in the control. SLCC (exon 5-11 skipping), but not transcriptional product from the allele with 851del4 mutation, was identified in the 851del4 mutation carrier.
CONCLUSIONSThis study demonstrated that the entire coding region of SLC25A13 cDNA can be successfully amplified from two cultured human amniocytes, and revealed exon 5-11 skipping as a novel SLC25A13 transcript. Normal mRNA predominated in the transcripts in normal control and 851del4 mutation carrier, suggesting that the two fetuses were not at risk for NICCD. These SLC25A13 transcription features provided laboratory evidence for prenatal diagnosis of NICCD.
Amniotic Fluid ; cytology ; metabolism ; Calcium-Binding Proteins ; deficiency ; Cholestasis, Intrahepatic ; diagnosis ; Cloning, Molecular ; Female ; Humans ; Mitochondrial Membrane Transport Proteins ; genetics ; Organic Anion Transporters ; deficiency ; Polymerase Chain Reaction ; Pregnancy ; Prenatal Diagnosis ; methods ; RNA, Messenger ; analysis ; Sequence Analysis, DNA ; Transcription, Genetic
8.Improving the diagnostic method for the SLC25A13 gene 851del4 mutation and analysis of the common mutation frequencies in Quanzhou area.
Hong-zhi GAO ; Qiu-lan LI ; Xiang-long ZHUANG ; Kobayashi KEIKO ; Ushikai MIHARU ; Saheki TAKEYORI ; Wei-peng HU ; Chang-wen ZHOU ; Ling LIN
Chinese Journal of Medical Genetics 2010;27(6):626-630
OBJECTIVETo ascertain whether the carrier rate is high in Quanzhou which is next to Taiwan in South of the Yangtze River.
METHODSPopulation analysis of three SLC25A13 mutations, i.e. 851del4, 1638-1660 dup, and IVS6+ 5G to A was carried out in 450 healthy individuals. DNA diagnostic method of 851del4 was improved by using PCR-restriction fragment length polymorphism( PCR-RFLP) with restriction enzyme HpyCH4 IV, and the results were confirmed by GeneScan method.
RESULTSSix carriers with 851del4, 3 with 1638-1660 dup and 3 with IVS6+ 5G to A was found.
CONCLUSIONThe high carrier rate (0.027, 12/450) obtained from testing of only three mutations indicated that there must be a certain number of patients with citrin deficiency in Quanzhou, even in Fujian. Therefore, it is important for physicians in Quanzhou, Fujian province to learn about citrin deficiency, and to diagnose and treat the patients correctly.
Asian Continental Ancestry Group ; genetics ; Base Sequence ; Calcium-Binding Proteins ; deficiency ; China ; DNA Mutational Analysis ; methods ; Female ; Humans ; Male ; Mitochondrial Membrane Transport Proteins ; genetics ; Organic Anion Transporters ; deficiency ; Polymorphism, Single Nucleotide ; genetics ; Sequence Deletion ; genetics
9.Neonatal intrahepatic cholestasis caused by citrin deficiency: a histopathologic study of 10 cases.
Guang-yu JIANG ; Zhao-ming CHENG ; Kai-shan LIU
Chinese Journal of Pathology 2012;41(7):452-455
OBJECTIVETo investigate the diagnostic value of histopathological changes in the liver of patients with neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD).
METHODSLiver specimens from 10 cases of NICCD were evaluated by hematoxylin-eosin stain, histochemistry and immunohistochemistry (EnVision method). SLC25A13 mutation analysis was performed to correlate with histopathology.
RESULTSMost specimens showed varying degrees of fat deposition in hepatocytes, necrotic inflammation, cholestasis and fibrosis (so-called tetralogy). The combination of the above four histological changes was highly characteristic for NICCD. With the progression of the disease, hepatic fibrosis deteriorated and ultimately led to cirrhosis.
CONCLUSIONSNICCD should be suspected in the presence of cholestasis during infancy. A liver biopsy must be performed to rule out other liver diseases. The tetralogy of the hepatic histopathological changes has a highly diagnostic value for NICCD, which is also practical for accurately assessing the degree of inflammation and fibrosis, and similarly the progression of hepatic cirrhosis.
Biopsy ; Calcium-Binding Proteins ; deficiency ; genetics ; metabolism ; Cholestasis, Intrahepatic ; etiology ; genetics ; pathology ; Disease Progression ; Female ; Hepatocytes ; pathology ; Humans ; Infant ; Liver ; pathology ; Liver Cirrhosis ; pathology ; Male ; Mitochondrial Membrane Transport Proteins ; genetics ; Mutation ; Organic Anion Transporters ; deficiency ; genetics ; metabolism
10.Identification and diagnosis of three novel mutations in SLC25A13 gene of neonatal intrahepatic cholestasis caused by citrin deficiency.
Yuan-zong SONG ; Jian-sheng SHENG ; Miharu USHIKAI ; Wuh-liang HWU ; Chun-hua ZHANG ; Keiko KOBAYASHI
Chinese Journal of Pediatrics 2008;46(6):411-415
OBJECTIVENeonatal intrahepatic cholestasis caused by citrin deficiency (NICCD, OMIM #605814) is a novel autosomal recessive disease caused by mutations in the gene SLC25A13 that encodes for citrin, a liver-type aspartate/glutamate carrier located in the mitochondrial inner membrane. SLC25A13 was cloned in 1999 by Kobayashi et al at Kagoshima University in Japan, and until now, most of the NICCD patients reported in the world were Japanese. Most of the Chinese NICCD patients diagnosed by genetic analysis had the same SLC25A13 mutations as Japanese, however, in some cases, known mutations were not detected. This research aimed to identify novel SLC25A13 mutations in Chinese NICCD patients and to explore the experimental conditions for their genetic diagnosis.
METHODSGenomic DNA was extracted from blood samples of 3 NICCD patients from Taiwan (P757), Guangdong (P1194) and Hebei province (P1443) of China, respectively, and all the 18 exons and their flanking sequences of SLC25A13 gene were sequenced. Furthermore, the identified novel mutations were diagnosed by amplification with PCR, digestion with corresponding restriction endonuclease, and agarose gel electrophoresis.
RESULTSThree novel mutations identified in SLC25A13 gene of the 3 NICCD patients were an abnormal splicing IVS7-2A > G (P757), a missense A541D (c.1622C > A, P1194) and a nonsense R319X (c.955C > T, P1443). The PCR-restriction fragment length polymorphism (RFLP) procedures for their genetic diagnosis were also established, with specific fragments on electrophoresis after digestion of the PCR products with three different restriction endonucleases Msp I, Hpy188I and Taq I, respectively.
CONCLUSIONSSo far as we know, the three novel mutations in SLC25A13 gene of Chinese NICCD patients were first identified, suggesting that SLC25A13 mutation distributed in Chinese population is somewhat different from that in Japanese. Moreover, the PCR-RFLP diagnostic procedures established in this research provide valuable tools not only for the genetic diagnosis of NICCD but also for further molecular epidemiologic investigations in Chinese population.
Asian Continental Ancestry Group ; genetics ; Base Sequence ; Calcium-Binding Proteins ; deficiency ; Child, Preschool ; Cholestasis, Intrahepatic ; diagnosis ; etiology ; genetics ; Female ; Humans ; Infant ; Male ; Mitochondrial Membrane Transport Proteins ; genetics ; Molecular Sequence Data ; Mutation ; Organic Anion Transporters ; deficiency