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Gene & Protein in Disease

ORIGINAL RESEARCH ARTICLE
Identifying regulatory variants in Indian Wilson’s

disease patients with missing heritability

Shubhrajit Roy 1 , Sreyashi Bhattacharya 2 , Arpan Saha 2 , Asif Iqbal 2 ,
Sampurna Ghosh 2 , Debmalya Sengupta 2 , Shyamal Kumar Das ,
3
4
5
Prasanta Kumar Gangopadhyay , Ashish Bavdekar , Kunal Ray 6 ,
Jharna Ray 1 , and Mainak Sengupta *
2
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

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
*Corresponding author: an established bioinformatic pipeline to identify and screen cis-regulatory elements
Mainak Sengupta
(msgntcs@caluniv.ac.in) of ATP7B in WD patients with missing heritability through polymerase chain reaction
sequencing. Although no pathogenic variants were identified, our analysis revealed
Citation: Roy S, Bhattacharya S,
Saha A, et al. Identifying regulatory two heterozygous single nucleotide polymorphisms (rs2181891 and rs747781) in two
variants in Indian Wilson’s disease patients. Notably, rs2181891 showed strong regulatory potential with a RegulomeDB
patients with missing heritability. score of 1d. The genotype-specific expression profile for rs2181891 revealed it to be
Gene Protein Dis. 2025;4(2):7503.
doi: 10.36922/gpd.7503 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
Received: December 13, 2024 associated with higher expression of ATP7B, making it unlikely to contribute to the
Revised: January 29, 2025
Accepted: February 13, 2025 WD phenotype. This novel study is the first to identify and screen ATP7B cis-regulatory
Published online: March 13, 2025 elements in Indian WD patients with missing heritability.
Copyright: © 2025 Author(s).
This is an Open-Access article
distributed under the terms of the Keywords: Wilson’s disease; ATP7B; Cis-regulatory elements; Missing heritability
Creative Commons Attribution
License, permitting distribution,
and reproduction in any medium,
provided the original work is
properly cited. 1. Introduction
Publisher’s Note: AccScience Wilson’s disease (WD) is a rare autosomal recessive copper metabolism disorder
Publishing remains neutral with characterized by abnormal copper deposition in tissues such as the liver, brain, eye,
regard to jurisdictional claims in 1,2
published maps and institutional kidney, and heart. The prevalence of WD ranges from 1 in 30,000 to 1 in 100,000
affiliations. individuals. WD is caused by mutations in the ATP7B gene, which encodes a copper-
1

Volume 4 Issue 2 (2025) 1 doi: 10.36922/gpd.7503