Complex ATP7B mutation patterns in Wilson disease and evaluation of a yeast model for functional analysis of variants

Abstract

Wilson disease (WD) is a rare autosomal recessive genetic disorder that is associated with various mutations in the ATP7B gene. Although ATP7B variants are frequently identified, the exact mutation patterns remain unknown because of the absence of pedigree studies, and the functional consequences of individual ATP7B variants remain to be clarified. In this study, we recruited 65 clinically diagnosed WD patients from 60 unrelated families. Pedigree analysis showed that besides several ATP7B homozygous variants (8/65, 12.3%), compound heterozygous variants (43/65, 66.2%) were present in the majority of WD patients. There were 20% of the patients had one (12/65, 18.5%) or multiple (1/65, 1.5%) variants in only a single allele, characterized by a high ratio of splicing or frameshift variants. Nine ATP7B variants were cloned into the pAG426GPD yeast expression vector to evaluate their functional consequences, and the results suggested different degrees of functional disruption from mild or uncertain to severe, consistent with the corresponding phenotypes. Our study revealed the complex ATP7B mutation patterns in WD patients and the applicability of a yeast model system to the Human Mutation. 2019;40:552-565. wileyonlinelibrary.com/journal/humu 552 |

Targeting Copper Homeostasis Improves Functioning of vps13Δ Yeast Mutant Cells, a Model of VPS13-Related Diseases

“…CCC2 encodes an ATPase, which transports copper to the Golgi apparatus [13,14]. The cDNA of ATP7A and ATP7B complements CCC2 deletion [15][16][17][18], and the yeast system is used to study pathogenic mutations in ATP7A and ATP7B [19][20][21][22]. Lastly, ion regulation is well characterised in yeast [23]; therefore, yeast could be used for studying disturbances of ion homeostasis including copper homeostasis.…”

RNA splicing alteration in the response to platinum chemotherapy in ovarian cancer: A possible biomarker and therapeutic target

“…This evidence suggests that splicing of ATP7A could also contribute to the response to PT and/or the onset of PT‐resistance, a possibility that certainly merits to be better investigated. Similar evidences are present for structurally and functionally highly homologous copper‐transporting ATPase ATP7B, whose mutations, including those at splice sites, are the cause of Wilson disease, another copper metabolism disorder leading to an excess of copper stored in tissues 105,106 . ATP7B has been also associated with PT resistance, although the role of AS in this function of ATP7B has not been determined yet 107 .…”

Insertion of LINE-1 Retrotransposon Inducing Exon Inversion Causes a Rotor Syndrome Phenotype

“…Here, for the first time, we report SLCO1B1 and SLCO1B3 gene mutations in Chinese patients with Rotor syndrome. Unlike several other hereditary liver metabolic diseases, such as Wilson disease and hereditary hemochromatosis (Lv et al, 2016;Li et al, 2019), the hotspots for SLCO1B1 and SLCO1B3 mutations are quite similar between different populations. We identified one nonsense variant (SLCO1B1, c.757C > T, p.R253X) and one splicing variant (SLCO1B3, c.1747+1G > A) in patient R1, and one nonsense variant (SLCO1B1, c.1738C > T, p.R580X) and an exon 4 inversion in the SLCO1B3 gene of patient R2.…”