AccScience Publishing / GPD / Online First / DOI: 10.36922/gpd.7503
ORIGINAL RESEARCH ARTICLE

Identifying regulatory variants in Indian Wilson’s disease patients with missing heritability

Shubhrajit Roy1 Sreyashi Bhattacharya2 Arpan Saha2 Asif Iqbal2 Sampurna Ghosh2 Debmalya Sengupta2 Shyamal Kumar Das3 Prasanta Kumar Gangopadhyay4 Ashish Bavdekar5 Kunal Ray6 Jharna Ray1 Mainak Sengupta2*
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1 S. N. Pradhan Centre for Neurosciences, University of Calcutta, Kolkata, West Bengal, India
2 Department of Genetics, University of Calcutta, Kolkata, West Bengal, India
3 Department of Neurology, Bangur Institute of Neurosciences, Kolkata, West Bengal, India
4 Department of Neuro-Medicine, National Medical College, Kolkata, West Bengal, India
5 Department of Paediatrics, KEM Hospital, Pune, Maharashtra, India
6 ATGC Diagnostics Pvt. Ltd., Kolkata, West Bengal, India
Submitted: 13 December 2024 | Revised: 29 January 2025 | Accepted: 13 February 2025 | Published: 13 March 2025
© 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
Abstract

Wilson’s disease (WD) is a rare autosomal recessive copper metabolism disorder that primarily affects hepatic and neuronal tissues. The condition is caused by mutations in the ATP7B gene. Our group conducted extensive molecular genetic studies, identifying 13 clinically diagnosed Indian WD patients lacking the coding variant of ATP7B and 17 patients with a single mutated allele. We hypothesize that in these patients, unidentified mutations may reside in cis-regulatory elements of ATP7B or that a WD-like phenotype results from the cumulative effect of hypofunctional alleles of other key genes in the copper metabolism pathway. In this study, we employed an established bioinformatic pipeline to identify and screen cis-regulatory elements of ATP7B in WD patients with missing heritability through polymerase chain reaction sequencing. Although no pathogenic variants were identified, our analysis revealed two heterozygous single nucleotide polymorphisms (rs2181891 and rs747781) in two patients. Notably, rs2181891 showed strong regulatory potential with a RegulomeDB score of 1d. The genotype-specific expression profile for rs2181891 revealed it to be an expression quantitative trait locus for ATP7B in the cerebellum. In addition, the Genotype-Tissue Expression portal data suggest that the T allele of rs2181891 is associated with higher expression of ATP7B, making it unlikely to contribute to the WD phenotype. This novel study is the first to identify and screen ATP7B cis-regulatory elements in Indian WD patients with missing heritability.

Graphical abstract
Keywords
Wilson’s disease
ATP7B
Cis-regulatory elements
Missing heritability
Funding
Shubhrajit Roy was supported by the University Grants Commission Junior Research fellowship (UGC-JRF) from UGC, Govt. of India.
Conflict of interest
The authors declare that they have no conflicts of interest.
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