Wilson disease (novel ATP7B variants) with concomitant FLNC-related cardiomyopathy.
Ontology highlight
ABSTRACT:
SUBMITTER: Imai T
PROVIDER: S-EPMC11362149 | biostudies-literature | 2024 Aug
REPOSITORIES: biostudies-literature
Publications
Wilson disease (novel ATP7B variants) with concomitant FLNC-related cardiomyopathy.
Imai Takeshi T Mitsuhashi Satomi S Isahaya Kenji K Shibata Soichiro S Kawai Yosuke Y Omae Yosuke Y Tokunaga Katsushi K Yamano Yoshihisa Y
Human genome variation 20240829 1
We report a case of Wilson disease (WD) with dilated cardiomyopathy in which whole-genome sequencing (WGS) revealed the rare co-occurrence of two novel compound heterozygous ATP7B pathogenic variants (NM_001005918.3:c.2250del/p.N751Tfs*9 and c.3496C>T/p.L1166F) and a known FLNC pathogenic variant. Our results highlight the usefulness of WGS, even in the diagnosis of well-characterized genetic diseases such as WD. ...[more]
Similar Datasets
Project description:Background: Diagnosis of rare Wilson disease (WD) in pediatric patients is difficult, in particular when hepatic manifestation is absent. Genetic analysis of ATP7B represents the single major determinant of the diagnostic scoring system in WD children having mild symptoms. Objectives: To assess the impact of molecularly expressed ATP7B gene products in order to assist diagnosis of Wilson disease in pediatric patients having a novel mutation and subtle neuropsychiatric disease. Methods: The medical history, clinical presentation, biochemical parameters, and the genetic analysis of ATP7B were determined. Due to ambiguous clinical and biochemical findings and identification of a novel compound ATP7B mutation with unknown disease-causing status, a molecular analysis of the ATP7B gene products in a previously well characterized cell model was performed. Results: The ATP7B variants were transgenically expressed and the respective gene function molecularly characterized. Despite normal mRNA expression, low ATP7B protein expression of the mutants p.L168P and p.S1423N was observed (34.3 ± 8% and 66.0 ± 8%, respectively). Copper exposure did not result in decreased viability of transgenic cells as compared to wild type. Intracellular copper accumulation was reduced (≤47.9 ± 8%) and intracellular protein trafficking was impaired. Conclusion: Our report suggests that functional characterization of novel ATP7B mutants can assist diagnosis; however mild functional impairments of ATP7B variants may hamper the value of such approaches.
| S-EPMC5937294 | biostudies-literature
Project description:BACKGROUND & AIMS:Wilson disease is a severe disorder of copper metabolism caused by mutations in ATP7B, which encodes a copper-transporting adenosine triphosphatase. The disease presents with a variable phenotype that complicates the diagnostic process and treatment. Little is known about the mechanisms that contribute to the different phenotypes of the disease. METHODS:We analyzed 28 variants of ATP7B from patients with Wilson disease that affected different functional domains; the gene products were expressed using the baculovirus expression system in Sf9 cells. Protein function was analyzed by measuring catalytic activity and copper ((64)Cu) transport into vesicles. We studied intracellular localization of variants of ATP7B that had measurable transport activities and were tagged with green fluorescent protein in mammalian cells using confocal laser scanning microscopy. RESULTS:Properties of ATP7B variants with pathogenic amino-acid substitution varied greatly even if substitutions were in the same functional domain. Some variants had complete loss of catalytic and transport activity, whereas others lost transport activity but retained phosphor-intermediate formation or had partial losses of activity. In mammalian cells, transport-competent variants differed in stability and subcellular localization. CONCLUSIONS:Variants in ATP7B associated with Wilson disease disrupt the protein's transport activity, result in its mislocalization, and reduce its stability. Single assays are insufficient to accurately predict the effects of ATP7B variants the function of its product and development of Wilson disease. These findings will contribute to our understanding of genotype-phenotype correlation and mechanisms of disease pathogenesis.
| S-EPMC3461965 | biostudies-literature
Project description:BackgroundFLNC gene variants have predominantly been reported in adult populations with cardiomyopathies, and early-onset cases are less common. The genotype-phenotype relationship indicates that dilated cardiomyopathy (DCM) is often associated with FLNC truncating variants.MethodsWe conducted a comprehensive genetic analysis using next generation sequencing (NGS) to identify FLNC variants in patients with cardiovascular conditions. Detailed phenotypic and variant analyses were performed to characterize the clinical features and genetic alterations. Minigene assays and structural modeling were used to investigate the pathogenicity caused by the identified variants.ResultsIn a cohort of 58 patients, novel heterozygous FLNC variants, c.3962A > T (p.Glu1321Val) and c.7543C > T (p.Leu2515Phe), were identified in patients presenting with dilated and mixed restrictive/hypertrophic cardiomyopathies, respectively. The c.3962A > T variant disrupted normal splicing, as demonstrated through the splicing prediction tool and minigene studies, further emphasizing its pathogenic potential.ConclusionFor missense variants of FLNC in patients with DCM, the splicing effect of the variant should be carefully checked. Early detection and intervention are crucial given the high risk of sudden cardiac death and severe cardiac complications.
| S-EPMC11520881 | biostudies-literature
Project description:ATP7A and ATP7B, two homologous copper-transporting P1B-type ATPases, play crucial roles in cellular copper homeostasis, and mutations cause Menkes and Wilson diseases, respectively. ATP7A/B contains a P-type ATPase core consisting of a membrane transport domain and three cytoplasmic domains, the A, P, and N domains, and a unique amino terminus comprising six consecutive metal-binding domains. Here, we present a cryo-electron microscopy structure of frog ATP7B in a copper-free state. Interacting with both the A and P domains, the metal-binding domains are poised to exert copper-dependent regulation of ATP hydrolysis coupled to transmembrane copper transport. A ring of negatively charged residues lines the cytoplasmic copper entrance that is presumably gated by a conserved basic residue sitting at the center. Within the membrane, a network of copper-coordinating ligands delineates a stepwise copper transport pathway. This work provides the first glimpse into the structure and function of ATP7 proteins and facilitates understanding of disease mechanisms and development of rational therapies.
| S-EPMC8896786 | biostudies-literature
Project description:BackgroundWilson disease (OMIM # 277900) is a autosomal recessive disorder characterized by accumulation of copper in liver and brain. The accumulation of copper resulting in oxidative stress and eventually cell death. The disease has an onset in a childhood and result in a significant neurological impairment or require lifelong treatment. Another serious consequence of the disease is the development of liver damage and acute liver failure leading to liver transplant. The disorder is caused by mutations in the ATP7B gene, encoding a P-type copper transporting ATPase.Case presentationWe performed genetic analysis of three unrelated patients from three different Vietnamese families. These patients had clinical features such as numbness of hands and feet, vomiting, insomnia, palsy, liver failure and Kayser-Fleischer (K-F) rings and were diagnosed with Wilson disease in the Human Genetics Department, Vietnam National Children's Hospital. The entire coding region and adjacent splice sites of ATP7B gene were amplified and sequenced by Sanger method. Sequencing data were analyzed and compared with the ATP7B gene sequence published in Ensembl (ENSG00000123191) by using BioEdit software to detect mutations.ConclusionsIn this study, five mutations in the ATP7B gene were found. Among of these, three mutations were novel: c.750_751insG (p.His251Alafs*19) in exon 2, c.2604delC (p.Pro868Profs*5) in exon 11, and c.3077 T > A (p.Phe1026Tyr) in exon 14. Our results of the mutations associated with Wilson disease might facilitate the development of effective treatment plans.
| S-EPMC6006946 | biostudies-literature
Project description:Wilson disease (WD) (OMIM# 277900) is an autosomal recessive inherited disorder characterized by excess copper (Cu) storage in different human tissues, such as the brain, liver, and the corneas of the eyes. It is a rare disorder that occurs in approximately 1 in 30,000 individuals. The clinical presentations of WD are highly varied, primarily consisting of hepatic and neurological conditions. WD is caused by homozygous or compound heterozygous mutations in the ATP7B gene. The diagnosis of the disease is complicated because of its heterogeneous phenotypes. The molecular genetic analysis encourages early diagnosis, treatment, and the opportunity to screen individuals at risk in the family. In this paper, we reported a case with a novel, hotspot-located mutation in WD. We have suggested that this mutation in the ATP7B gene might contribute to liver findings, progressing to liver failure with a loss of function effect. Besides this, if patients have liver symptoms in childhood and/or are children of consanguineous parents, WD should be considered during the evaluation of the patients.
| S-EPMC7912016 | biostudies-literature
Project description:Wilson Disease (WD) is an inborn error of copper metabolism inherited in an autosomal recessive manner caused by the mutations in the P-type ATPase gene (ATP7B). In this study, we screen and detect the mutations of the ATP7B gene in unrelated Chinese WD patients. A total of 68 individuals from ten provinces of China with WD were recruited. Of them, 43 were males and 25 were females, and their onset ages were from 1 to 48 years with a median onset age of 22.2 years. All the exons and exon/intron boundaries of ATP7B gene of the patients were sequenced and aligned to the referred ATP7B gene sequence. The results suggested that 66 of the 68 patents carried with at least one mutation and 48 different mutations were identified including 34 missense, one synonymous, two nonsense, two splicing, and nine frameshift mutations (five insertion and four deletion). Among these mutations, c.2333G>T, c.2310C>G, c.2975C>T, and c.3443T>C were the most prevalent mutants and c.2310C>G always linked with c.2333G>T. The eighth, 11(th), and 18(th) exons carried more mutations (6/48, 5/48, and 5/48, respectively) than others. After comparing with the mutations reported previously, 22 out of the 48 mutations were identified as novel mutations. A popular algorithm, Polyphen-2, was used to predict the effects of the amino-acid substitution due to the mutations on the structure and function of ATP7B function and the predicted results indicated that all the missense mutations were unfavorable except c.121A>G and c.748G>A. Phenotype/genotype correlation analysis suggested that the patients with c.2975C>T or c.3809A>G often presented WD features before 12 years old while the patients with c.3443T>C almost presented WD after 12 years old. This is the first time to identify the common mutations contributing to early onset age in Chinese WD patients. Our study will broaden our knowledge about ATP7B mutations in WD patients.
| S-EPMC4931180 | biostudies-literature
Project description:Wilson disease (WD) is a rare autosomal recessive disorder of copper metabolism typically presenting after 3 years of age. We describe a girl presenting with neonatal cholestasis rapidly progressing to end-stage liver disease. She presented hepatosplenomegaly, neurological impairment, Coombs-negative hemolytic anemia, central hypothyroidism. A patient-parents whole exome sequencing identified a homozygous state for ATP7B mutations causing WD in the proband (p.Gln7fs/p.His1069Gln) and her mother (p.His1069Gln/p.His1069Gln), who was then confirmed to have cirrhotic WD. A causative role of copper toxicity due to ATP7B loss of function was indicated by the presence of extrahepatic features of WD, consistent tests of copper metabolism-including a 7-fold increase in liver copper-and similarity of patient's liver gene expression profile and ultrastructure with that of WD models. This exceptionally early presentation could result from the combination of the ATP7B impairment and the intrauterine copper overload due to maternal undiagnosed WD.
| S-EPMC10191499 | biostudies-literature
Project description:BackgroundWilson disease is an autosomal recessive metabolic disorder resulting from accumulation of excess copper especially in the liver and brain. This disease is mainly characterized by hepatic disorders and less frequently by neuro-psychiatric disturbances. This recessive disease is due to mutation in ATP7B, which codes for an ATPase involved in copper-transport across the plasma membrane. Molecular diagnosis of WD is positive in approximately 98% of cases. Also, in few cases, WD patients present a single deleterious mutation (heterozygous) or no mutation after sanger and NGS standard sequencing analysis of ATP7B. Therefore, in these problematic WD cases, we hypothesized that deleterious mutations reside in intronic regions of ATP7B.MethodsComplete ATP7B gene was sequenced by Next Generation Sequencing including its promoter.ResultsFive unrelated families with Wilson disease shared the same novel, deep intronic NG_008806.1 (ATP7B_v001):c.2866-1521G>A variant in ATP7B. Analysis of RNA transcripts from primary fibroblasts of one patient confirmed the deleterious impact of the intronic variant on splicing and its likely pathologic effect in this compound heterozygote.ConclusionThis discovery of a novel intronic mutation in ATP7B has improved the molecular diagnosis of WD in the French patient cohort to greater than 98%. Thus, we recommend complete sequencing of ATP7B gene, including introns, as a molecular diagnostic approach in cases of clinically confirmed WD which lack pathogenic exon or promoter variants in one or both alleles.
| S-EPMC7549599 | biostudies-literature
Project description:The goal of the study was find the gene expression of diverse signaling pathways altered in Atp7b-/- mice (murine WD) liver as compared to control mice and how LXR agonist treatment will improve/ameliorate WD phenotype in Atp7b-/- mice. Activation of LXR/RXR using synthetic LXR agonist ameliorates liver inflammation and fibrosis in murine WD by changing gene expression.
2022-10-26 | GSE174015 | GEO