Wilson disease (WD) is an autosomal recessive disorder characterized by toxic accumulation of copper in the liver and subsequently in the brain and other organs. On the basis of sequence homology to known genes, the WD gene (ATP7B) appears to be a copper-transporting P-type ATPase. A search for ATP7B mutations in WD patients from five population samples, including 109 North American patients, revealed 27 distinct mutations, 18 of which are novel. A composite of published findings shows missense mutations in all exons-except in exons 1-5, which encode the six copper-binding motifs, and in exon 21, which spans the carboxy-terminus and the poly(A) tail. Over one-half of all WD mutations occur only rarely in any population sample. A splice-site mutation in exon 12 accounts for 3% of the WD mutations in our sample and produces an in-frame, 39-bp insertion in mRNA of patients homozygous, but not heterozygous, for the mutation. The most common WD mutation (His1069Glu) was represented in approximately 38% of all the WD chromosomes from the North American, Russian, and Swedish samples. In several population cohorts, this mutation deviated from Hardy-Weinberg equilibrium, with an overrepresentation of homozygotes. We did not find a significant correlation between His1069Glu homozygosity and several clinical indices, including age of onset, clinical manifestation, ceruloplasmin activity, hepatic copper levels, and the presence of Kayser-Fleischer rings. Finally, lymphoblast cell lines from individuals homozygous for His1069Glu and 4 other mutations all demonstrated significantly decreased copper-stimulated ATPase activity.
Download full-text PDF |
Source |
---|---|
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1715895 | PMC |
http://dx.doi.org/10.1086/514864 | DOI Listing |
Neurol Genet
February 2025
Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada.
Background And Objectives: Neonatal encephalopathy (NE) is characterized by an abnormal level of consciousness with or without seizures in the neonatal period. It affects 1-6/1,000 live term newborns. We applied genome sequencing (GS) in term newborns with NE to investigate the underlying genetic causes.
View Article and Find Full Text PDFNeurodegener Dis Manag
January 2025
Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA, USA.
Friedreich ataxia (FRDA) is a slowly progressive neurological disease resulting from decreased levels of the protein frataxin, a small mitochondrial protein that facilitates the synthesis of iron-sulfur clusters in the mitochondrion. It is caused by GAA (guanine-adenine-adenine) repeat expansions in the gene in 96% of patients, with 4% of patients carrying other mutations (missense, nonsense, deletion) in the gene. Compound heterozygote patients with one expanded GAA allele and a non-GAA repeat mutation can have subtle differences in phenotype from typical FRDA, including, in patients with selected missense mutations, both more severe features and less severe features in the same patient.
View Article and Find Full Text PDFMedicine (Baltimore)
November 2024
First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui, China.
This study investigates levels of cuproptosis markers in Wilson disease (WD) and their role in the occurrence and development of WD. We retrospectively collected clinical data from 76 patients with Leipzig score ≥ 4 hospitalized in the First Affiliated Hospital of Anhui University of Chinese Medicine from January 2023 to September 2023. The participants were given copper chelators (sodium dimercaptosulphonate (20 mg·kg-1), 4 courses of treatment, 32 days).
View Article and Find Full Text PDFLiver Int
February 2025
Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
Background And Aims: Porto-sinusoidal vascular disorder (PSVD) is a rare vascular liver disorder characterised by specific histological findings in the absence of cirrhosis, which is poorly understood in terms of pathophysiology. While elevated hepatic copper content serves as diagnostic hallmark in Wilson disease (WD), hepatic copper content has not yet been investigated in PSVD.
Methods: Patients with a verified diagnosis of PSVD at the Medical University of Vienna and available hepatic copper content at the time of diagnosis of PSVD were retrospectively included.
Objectives: To describe the epidemiology, patient characteristics and comorbidities in patients with Wilson disease (WD) in the USA.
Design: Retrospective, population-based study.
Setting: The study used the US Komodo claims database containing records regarding medical claims for over 120 million individuals.
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!