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Article ; Online: NR1H4 disease: rapidly progressing neonatal intrahepatic cholestasis and early death.

Li, Zhong-Die / Li, Yu-Chuan / Jing-Zhao / Wang, Jian-She / Xie, Xin-Bao

2024 Volume 19, Issue 1, Page(s) 171

Abstract: Background: Clinical studies on progressive familial intrahepatic cholestasis (PFIC) type 5 caused by mutations in NR1H4 are limited.: Methods: New patients with biallelic NR1H4 variants from our center and all patients from literature were ... ...

Abstract	Background: Clinical studies on progressive familial intrahepatic cholestasis (PFIC) type 5 caused by mutations in NR1H4 are limited. Methods: New patients with biallelic NR1H4 variants from our center and all patients from literature were retrospectively analyzed. Results: Three new patients were identified to be carrying five new variants. Liver phenotypes of our patients manifests as low-γ-glutamyl transferase cholestasis, liver failure and related complications. One patient underwent liver transplantation (LT) and survived, and two other patients died without LT. Nine other patients were collected through literature review. Twelve out of 13 patients showed neonatal jaundice, with the median age of onset being 7 days after birth. Reported clinical manifestations included cholestasis (13/13, 100%), elevated AFP (11/11, 100%), coagulopathy (11/11, 100%), hypoglycemia (9/13, 69%), failure to thrive (8/13, 62%), splenomegaly (7/13, 54%), hyperammonemia (7/13, 54%), and hepatomegaly (6/13, 46%). Six of 13 patients received LT at a median age of 6.2 months, and only one patient died of acute infection at one year after LT. Other 7 patients had no LT and died with a median age of 5 months (range 1.2-8). There were 8 patients with homozygous genotype and 5 patients with compound heterozygous genotype. In total, 13 different variants were detected, and 5 out of 12 single or multiple nucleotides variants were located in exon 5. Conclusions: We identified three newly-diagnosed patients and five novel mutations. NR1H4-related PFIC typically cause progressive disease and early death. LT may be the only lifesaving therapy leading to cure.
MeSH term(s)	Humans ; Infant, Newborn ; Infant ; Retrospective Studies ; Cholestasis, Intrahepatic/genetics ; Cholestasis, Intrahepatic/diagnosis ; Cholestasis, Intrahepatic/therapy ; Cholestasis/genetics
Language	English
Publishing date	2024-04-19
Publishing country	England
Document type	Journal Article
ZDB-ID	2225857-7
ISSN	1750-1172 ; 1750-1172
ISSN (online)	1750-1172
ISSN	1750-1172
DOI	10.1186/s13023-024-03166-1
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Article ; Online: Comprehensive Bile Acid Profiling of ABCB4-mutated Patients and the Prognostic Role of Taurine-conjugated 3α,6α,7α,12α-Tetrahydroxylated Bile Acid in Cholestasis.

Liu, Teng / Wang, Ren-Xue / Han, Jun / Li, Zhong-Die / Sheps, Jonathan A / Zheng, Li-Juan / Xu, Xiao-Xiao / Ling, Victor / Wang, Jian-She

Journal of clinical and translational hepatology

2023 Volume 12, Issue 2, Page(s) 151–161

Abstract: Background and aims: We asked if comprehensive bile acid profiling could provide insights into the physiopathology of : Methods: Serum bile acid profiles were evaluated in 13 : Results: The overall hydrophobicity indices of bile acids in : ... ...

Abstract	Background and aims: We asked if comprehensive bile acid profiling could provide insights into the physiopathology of Methods: Serum bile acid profiles were evaluated in 13 Results: The overall hydrophobicity indices of bile acids in Conclusions: Tauro-THBA concentration may be a biomarker for predicting the clinical outcome in low gamma-glutamyl transferase intrahepatic cholestasis patients.
Language	English
Publishing date	2023-09-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	3019822-7
ISSN	2310-8819 ; 2225-0719
ISSN (online)	2310-8819
ISSN	2225-0719
DOI	10.14218/JCTH.2023.00095
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Article ; Online: Recurrent AKR1D1 c.580-13T>A Variant: A Cause of Δ

Zhao, Jing / Qiu, Yi-Ling / Wang, Li / Li, Zhong-Die / Xie, Xin-Bao / Lu, Yi / Setchell, Kenneth D R / Cheng, Ye / Xing, Qing-He / Wang, Jian-She

The Journal of molecular diagnostics : JMD

2023 Volume 25, Issue 4, Page(s) 227–233

Abstract: ... ...

Abstract	Δ
MeSH term(s)	Infant ; Humans ; Infant, Newborn ; Bile Acids and Salts ; Liver ; Oxidoreductases/genetics ; Oxidoreductases/metabolism ; Infant, Newborn, Diseases ; Ketosteroids/metabolism
Chemical Substances	Bile Acids and Salts ; Oxidoreductases (EC 1.-) ; Ketosteroids
Language	English
Publishing date	2023-02-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2000060-1
ISSN	1943-7811 ; 1525-1578
ISSN (online)	1943-7811
ISSN	1525-1578
DOI	10.1016/j.jmoldx.2023.01.004
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Article: Novel Melanocortin 2 Receptor Variant in a Chinese Infant With Familial Glucocorticoid Deficiency Type 1, Case Report and Review of Literature.

Abuduxikuer, Kuerbanjiang / Li, Zhong-Die / Xie, Xin-Bao / Li, Yu-Chuan / Zhao, Jing / Wang, Jian-She

Frontiers in endocrinology

2019 Volume 10, Page(s) 359

Abstract: Familial glucocorticoid deficiency type 1 (FGD1) is an autosomal recessive disorder caused by mutations in the melanocortin 2 receptor ( ...

Abstract	Familial glucocorticoid deficiency type 1 (FGD1) is an autosomal recessive disorder caused by mutations in the melanocortin 2 receptor (
Language	English
Publishing date	2019-06-06
Publishing country	Switzerland
Document type	Case Reports
ZDB-ID	2592084-4
ISSN	1664-2392
ISSN	1664-2392
DOI	10.3389/fendo.2019.00359
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Article ; Online: Poly-hydroxylated bile acids and their prognostic roles in Alagille syndrome.

Wang, Meng-Xuan / Han, Jun / Liu, Teng / Wang, Ren-Xue / Li, Li-Ting / Li, Zhong-Die / Yang, Jun-Cong / Liu, Lang-Li / Lu, Yi / Xie, Xin-Bao / Gong, Jing-Yu / Li, Shi-Yu / Zhang, Lei / Ling, Victor / Wang, Jian-She

World journal of pediatrics : WJP

2023 Volume 19, Issue 7, Page(s) 652–662

Abstract: Background: The liver manifestations of Alagille syndrome (ALGS) are highly variable, and factors affecting its prognosis are poorly understood. We asked whether the composition of bile acids in ALGS patients with good clinical outcomes differs from ... ...

Abstract	Background: The liver manifestations of Alagille syndrome (ALGS) are highly variable, and factors affecting its prognosis are poorly understood. We asked whether the composition of bile acids in ALGS patients with good clinical outcomes differs from that in patients with poor outcomes and whether bile acids could be used as prognostic biomarkers. Methods: Blood for bile acid profiling was collected from genetically confirmed JAG1-associated ALGS patients before one year of age. A good prognosis was defined as survival with native liver and total bilirubin (TB) < 85.5 μmol/L, while a poor prognosis was defined as either liver transplantation, death from liver failure, or TB ≥ 85.5 μmol/L at the last follow-up. Results: We found that the concentrations of two poly-hydroxylated bile acids, tauro-2β,3α,7α,12α-tetrahydroxylated bile acid (THBA) and glyco-hyocholic acid (GHCA), were significantly increased in patients with good prognosis compared to those with poor prognosis [area under curve (AUC) = 0.836 and 0.782, respectively] in the discovery cohort. The same trend was also observed in the molar ratios of GHCA to glyco- chenodeoxycholic acid (GCDCA) and tetrahydroxylated bile acid (THCA) to tauro-chenodeoxycholic acid (TCDCA) (both AUC = 0.836). A validation cohort confirmed these findings. Notably, tauro-2β,3α,7α,12α-THBA achieved the highest prediction accuracy of 88.00% (92.31% sensitivity and 83.33% specificity); GHCA at > 607.69 nmol/L was associated with native liver survival [hazard ratio: 13.03, 95% confidence interval (CI): (2.662-63.753), P = 0.002]. Conclusions: We identified two poly-hydroxylated bile acids as liver prognostic biomarkers of ALGS patients. Enhanced hydroxylation of bile acids may result in better clinical outcomes.
MeSH term(s)	Humans ; Bile Acids and Salts ; Alagille Syndrome/diagnosis ; Prognosis ; Chenodeoxycholic Acid ; Biomarkers
Chemical Substances	Bile Acids and Salts ; Chenodeoxycholic Acid (0GEI24LG0J) ; Biomarkers
Language	English
Publishing date	2023-01-19
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2236681-7
ISSN	1867-0687 ; 1708-8569
ISSN (online)	1867-0687
ISSN	1708-8569
DOI	10.1007/s12519-022-00676-5
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Article ; Online: Association of novel TMEM67 variants with mild phenotypes of high gamma-glutamyl transpeptidase cholestasis and congenital hepatic fibrosis.

Qiu, Yi-Ling / Wang, Li / Huang, Min / Lian, Min / Wang, Fengbin / Gong, Ying / Ma, Xiong / Hao, Chen-Zhi / Zhang, Jing / Li, Zhong-Die / Xing, Qing-He / Cao, Muqing / Wang, Jian-She

Journal of cellular physiology

2022 Volume 237, Issue 6, Page(s) 2713–2723

Abstract: TMEM67 (mecklin or MKS3) locates in the transition zone of cilia. Dysfunction of TMEM67 disrupts cilia-related signaling and leads to developmental defects of multiple organs in humans. Typical autosomal recessive TMEM67 defects cause partial overlapping ...

Abstract	TMEM67 (mecklin or MKS3) locates in the transition zone of cilia. Dysfunction of TMEM67 disrupts cilia-related signaling and leads to developmental defects of multiple organs in humans. Typical autosomal recessive TMEM67 defects cause partial overlapping phenotypes, including abnormalities in the brain, eyes, liver, kidneys, bones, and so forth. However, emerging reports of isolated nephronophthisis suggest the possibility of a broader phenotype spectrum. In this study, we analyzed the genetic data of cholestasis patients with no obvious extrahepatic involvement but with an unexplained high level of gamma-glutamyl transpeptidase (GGT). We identified five Han Chinese patients from three unrelated families with biallelic nonnull low-frequency TMEM67 variants. All variants were predicted pathogenic in silico, of which p. Arg820Ile and p. Leu144del were previously unreported. In vitro studies revealed that the protein levels of the TMEM67 variants were significantly decreased; however, their interaction with MKS1 remained unaffected. All the patients, aged 7-39 years old, had silently progressive cholestasis with elevated GGT but had normal bilirubin levels. Histological studies of liver biopsy of patients 1, 3, and 5 showed the presence of congenital hepatic fibrosis. We conclude that variants in TMEM67 are associated with a mild phenotype of unexplained, persistent, anicteric, and high GGT cholestasis without typical symptoms of TMEM67 defects; this possibility should be considered by physicians in gastroenterology and hepatology.
MeSH term(s)	Cholestasis/genetics ; Genetic Diseases, Inborn ; Humans ; Liver Cirrhosis/genetics ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Phenotype ; gamma-Glutamyltransferase/genetics
Chemical Substances	Membrane Proteins ; TMEM67 protein, human ; gamma-Glutamyltransferase (EC 2.3.2.2)
Language	English
Publishing date	2022-05-27
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3116-1
ISSN	1097-4652 ; 0021-9541
ISSN (online)	1097-4652
ISSN	0021-9541
DOI	10.1002/jcp.30788
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Article ; Online: Defining pathogenicity of NOTCH2 variants for diagnosis of Alagille syndrome type 2 using a large cohort of patients.

Li, Zhong-Die / Abuduxikuer, Kuerbanjiang / Wang, Li / Hao, Chen-Zhi / Zhang, Jing / Wang, Meng-Xuan / Li, Li-Ting / Qiu, Yi-Ling / Xie, Xin-Bao / Lu, Yi / Wang, Jian-She

Liver international : official journal of the International Association for the Study of the Liver

2022 Volume 42, Issue 8, Page(s) 1836–1848

Abstract: Background and aims: Alagille syndrome (ALGS) type 2 caused by mutations in NOTCH2 has genotypic and phenotypic heterogeneity. Diagnosis in some atypical patients with isolated hepatic presentation could be missed.: Methods: Using 2087 patients with ... ...

Abstract	Background and aims: Alagille syndrome (ALGS) type 2 caused by mutations in NOTCH2 has genotypic and phenotypic heterogeneity. Diagnosis in some atypical patients with isolated hepatic presentation could be missed. Methods: Using 2087 patients with paediatric liver manifestations, NOTCH2 allele frequencies, in-silico prediction, protein domains and clinical features were analysed to define the pathogenicity of NOTCH2 variants for diagnosis of ALGS type 2. Results: Among 2087 patients with paediatric liver manifestations, significantly more NOTCH2 variants were absent in gnomAD in patients with elevated γ-glutamyltransferase (GGT) (p = .041). Significantly more NOTCH2 variants which were absent in gnomAD were located in protein functional domains (p = .038). When missense variants were absent in gnomAD and predicted to be pathogenic by at least three out of seven in-silico tools, they were found to be significantly associated with liver manifestations with elevated GGT (p = .003). Comparing this to patients with likely benign (LB) variants, the patients with likely-pathogenic (LP) variants have significantly more liver manifestations with elevated GGT (p = .0001). Significantly more patients with LP variants had extra-hepatic phenotypes of ALGS compared with those patients with LB variants (p = .0004). Conclusion: When NOTCH2 variants are absent in gnomAD, null variants and missense variants which were predicted to be pathogenic by at least three in-silico tools could be considered pathogenic in patients with high GGT chronic liver diseases.
MeSH term(s)	Alagille Syndrome/diagnosis ; Alagille Syndrome/genetics ; Humans ; Jagged-1 Protein/genetics ; Jagged-1 Protein/metabolism ; Mutation ; Phenotype ; Receptor, Notch2/genetics ; Receptor, Notch2/metabolism ; Virulence
Chemical Substances	Jagged-1 Protein ; NOTCH2 protein, human ; Receptor, Notch2
Language	English
Publishing date	2022-05-23
Publishing country	United States
Document type	Journal Article
ZDB-ID	2102783-3
ISSN	1478-3231 ; 1478-3223
ISSN (online)	1478-3231
ISSN	1478-3223
DOI	10.1111/liv.15292
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Zs.A 1632: Show issues

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Article: NBAS disease: 14 new patients, a recurrent mutation, and genotype-phenotype correlation among 24 Chinese patients.

Li, Zhong Die / Abuduxikuer, Kuerbanjiang / Zhang, Jing / Yang, Ye / Qiu, Yi-Ling / Huang, Yuge / Xie, Xin-Bao / Lu, Yi / Wang, Jian-She

Hepatology research : the official journal of the Japan Society of Hepatology

2020 Volume 50, Issue 11, Page(s) 1306–1315

Abstract: Aim: Neuroblastoma amplified sequence (NBAS)-associated disease has a wide phenotypic spectrum, including infantile liver failure syndrome type 2 (ILFS2, OMIM #616483), short stature with optic nerve atrophy and Pelger-Huët anomaly (SOPH) syndrome (OMIM ...

Abstract	Aim: Neuroblastoma amplified sequence (NBAS)-associated disease has a wide phenotypic spectrum, including infantile liver failure syndrome type 2 (ILFS2, OMIM #616483), short stature with optic nerve atrophy and Pelger-Huët anomaly (SOPH) syndrome (OMIM #614800), and a combined phenotype overlapping ILFS2 and SOPH syndrome. The mutation spectra of NBAS and its genotype-phenotype correlation among Chinese were not clear. Methods: Clinical and genetic data were retrospectively collected from the medical charts of patients with biallelic NBAS mutations, as well as from Chinese patients in previously published reports. Results: Fourteen new patients were identified, including 10 novel mutations: c.648-1G>A, c.2563_c.2577+5del/p.His855_Gln859del, c.3115C>T/p.Gln1039Ter, c.3284G>A/p.Trp1095Ter, c.2570C>T/p.Ala857Val, c.6859G>T/p.Asp2287Tyr, c.1028G>A/p.Ser343Asn, c.1177_1182delinsAGATAGA/p.Val393ArgfsTer2, c.3432_3435dupCAGT/p.Ala1146GlnfsTer14, and c.680_690dupACTGTTTCAGC/p.Phe231ThrfsTer35. All 14 patients presented as fever-triggered liver injury, including nine patients that satisfied the criteria of acute liver failure (ALF) in whom c.3596G>A/p.Cys1199Tyr occurred five times. Nine patients had extrahepatic manifestations including short stature, skeletal abnormalities, intellectual disability, ophthalmic abnormalities, low levels of serum immunoglobulins, facial dysmorphism, and cardiac abnormalities. Ten other Chinese patients were collected through a review of published works. Genotype-phenotype analysis in 24 Chinese patients revealed that the percentage of ALF patients with variants in the Sec39 domain was significantly higher than that in the C-terminal (100% vs. 12.5%, P = 0.000), and the percentage of multi-organ/system involvement in patients with variants in the Sec39 domain was significantly lower than that in the C-terminal (40% vs. 100%, P = 0.0128). Conclusions: We reported 14 new patients, 10 novel mutations, and a unique recurrent mutation. Correlation analysis indicated that the domain of missense and non-frameshift insertion/deletion mutations in NBAS protein is related to phenotype among Chinese patients.
Language	English
Publishing date	2020-08-31
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1387041-5
ISSN	1386-6346 ; 0928-4346
ISSN	1386-6346 ; 0928-4346
DOI	10.1111/hepr.13559
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Article ; Online: ABCB11 deficiency presenting as transient neonatal cholestasis: Correlation with genotypes and BSEP expression.

Li, Li-Ting / Li, Zhong-Die / Yang, Ye / Lu, Yi / Xie, Xin-Bao / Chen, Lian / Feng, Jia-Yan / Knisely, A S / Wang, Jian-She

Liver international : official journal of the International Association for the Study of the Liver

2020 Volume 40, Issue 11, Page(s) 2788–2796

Abstract: Background & aims: ABCB11 deficiency presenting in infancy is believed generally to manifest as persistent/progressive cholestasis. We describe a group of patients with biallelic ABCB11 variants whose disorder manifested as transient neonatal ... ...

Abstract	Background & aims: ABCB11 deficiency presenting in infancy is believed generally to manifest as persistent/progressive cholestasis. We describe a group of patients with biallelic ABCB11 variants whose disorder manifested as transient neonatal cholestasis (TNC). Methods: Neonatal intrahepatic cholestasis in 68 children (31 males) with biallelic predictedly pathogenic variants (PPV) in ABCB11 was classified as transient (TNC group, n = 23, 11 males), intermittent (benign recurrent intrahepatic cholestasis [BRIC] group, n = 3, 1 male) or persistent/ progressive (progressive familial intrahepatic cholestasis [PFIC] group, n = 42, 19 males). Clinical, genetic and bile salt export pump (BSEP) expression information was correlated with outcomes. Results: The median onset age of jaundice was 3 days (birth to 2 months) for the TNC group and 10.5 days (birth to 3 months) for the PFIC group (P = .034). The median length of follow-up of TNC patients was 44 months (12 months-168 months). At presentation, hepatobiliary-injury biomarker values were similar between the groups (P > .05). TNC patients (17/23) more often than PFIC patients (20/42, P = .041) harboured biallelic non-null variants (predicted not to terminate translation prematurely). TNC patient livers (7/7) more often than PFIC patient livers (5/16, P = .005) expressed immunohistochemically detectable BSEP. Kaplan-Meier analysis showed better prognosis for patients with BSEP expression (P = .009). Too few BRIC patients were available for statistical study. Conclusions: Neonatal cholestasis associated with biallelic PPV in ABCB11 can resolve temporarily or persistently in one third of cases. Resolution is more likely in patients with biallelic non-null PPV or with liver BSEP expression.
MeSH term(s)	ATP Binding Cassette Transporter, Subfamily B, Member 11/genetics ; ATP-Binding Cassette Transporters/genetics ; Child ; Cholestasis/genetics ; Cholestasis, Intrahepatic/diagnosis ; Cholestasis, Intrahepatic/genetics ; Genotype ; Humans ; Infant ; Infant, Newborn ; Male ; Mutation
Chemical Substances	ABCB11 protein, human ; ATP Binding Cassette Transporter, Subfamily B, Member 11 ; ATP-Binding Cassette Transporters
Language	English
Publishing date	2020-10-13
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2102783-3
ISSN	1478-3231 ; 1478-3223
ISSN (online)	1478-3231
ISSN	1478-3223
DOI	10.1111/liv.14642
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Article ; Online: TJP2 hepatobiliary disorders: Novel variants and clinical diversity.

Zhang, Jing / Liu, Lang-Li / Gong, Jing-Yu / Hao, Chen-Zhi / Qiu, Yi-Ling / Lu, Yi / Feng, Jia-Yan / Li, Jia-Qi / Li, Zhong-Die / Wang, Meng-Xuan / Xing, Qing-He / Knisely, A S / Wang, Jian-She

Human mutation

2019 Volume 41, Issue 2, Page(s) 502–511

Abstract: To assess the spectrum of pediatric clinical phenotypes in TJP2 disease, we reviewed records of our seven patients in whom intrahepatic cholestasis was associated with biallelic TJP2 variants (13; 12 novel) and correlated clinical manifestations with ... ...

Abstract	To assess the spectrum of pediatric clinical phenotypes in TJP2 disease, we reviewed records of our seven patients in whom intrahepatic cholestasis was associated with biallelic TJP2 variants (13; 12 novel) and correlated clinical manifestations with mutation type. The effect of a splicing variant was analyzed with a minigene assay. The effects of three missense variants were analyzed with protein expression in vitro. Our patients had both remitting and persistent cholestasis. Three exhibited growth retardation. Six responded to treatment with cholestyramine, ursodeoxycholic acid, or both. Two had cholecystolithiasis. None required liver transplantation or developed hepatocellular or cholangiocellular malignancy. None manifested extrahepatic disease not attributable to effects of cholestasis. The variant c.2180-5T>G resulted in exon 15 skipping with in-frame deletion of 32 amino acid residues in TJP2. The three missense variants decreased but did not abolish TJP2 expression. Patients with truncating or canonical splice-site variants had clinically more severe disease. TJP2 disease in children includes a full clinical spectrum of severity, with mild or intermittent forms as well as the severe and minimal forms hitherto described. Biallelic TJP2 variants must be considered in children with clinically intermittent or resolved intrahepatic cholestasis.
MeSH term(s)	Age of Onset ; Alleles ; Amino Acid Substitution ; Biopsy ; Cholestasis, Intrahepatic/diagnosis ; Cholestasis, Intrahepatic/genetics ; Computational Biology/methods ; Female ; Genetic Predisposition to Disease ; Genetic Variation ; Humans ; Infant ; Infant, Newborn ; Male ; Mutation ; Pedigree ; RNA Splicing ; Whole Exome Sequencing ; Zonula Occludens-2 Protein/genetics
Chemical Substances	TJP2 protein, human ; Zonula Occludens-2 Protein
Language	English
Publishing date	2019-11-28
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1126646-6
ISSN	1098-1004 ; 1059-7794
ISSN (online)	1098-1004
ISSN	1059-7794
DOI	10.1002/humu.23947
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