Wilson Disease Mutation Pattern with Genotype‐Phenotype Correlations from Western India: Confirmation of p.C271* as a Common Indian Mutation and Identification of 14 Novel Mutations

Abstract

SummaryWilson disease (WD) is an autosomal recessive disorder resulting from mutations in the ATP7B gene, with over 600 mutations described. Identification of mutations has made genetic diagnosis of WD feasible in many countries. The heterogeneity of ATP7B mutants is, however, yet to be identified in the Indian population. We analyzed the mutational pattern of WD in a large region of Western India. We studied patients (n = 52) for ATP7B gene mutations in a cohort of families with WD and also in first-degree relatives (n = 126). All 21 exon-intron boundaries of the WD gene were amplified and directly sequenced. We identified 36 different disease-causing mutations (31 exonic and five intronic splice site variants). Fourteen novel mutations were identified. Exons 2, 8, 13, 14, and 18 accounted for the majority of mutations (86.4%). A previously recognized mutation, p.C271 * , and the novel mutation p.E122fs, were the most common mutations with allelic frequencies of 20.2% and 10.6%, respectively. Frequent homozygous mutations (58.9%) and disease severity assessments allowed analysis of genotype-phenotype correlations. Our study significantly adds to the emerging data from other parts of India suggesting that p.C271 * may be the most frequent mutation across India, and may harbor a moderate to severely disabling phenotype with limited variability.

Characterization of mutation spectrum and identification of novel mutations in ATP7B gene from a cohort of Wilson disease patients: Functional and therapeutic implications

“…Three mutations including, c.2865+1G>A, p.(Trp1153Arg), and novel mutation p.(Asp642Tyr) were found to affect all the siblings of three different families, indicating their sporadic distribution. While c.2865+1G>A is a rare mutation having one incidence each from the Czech Republic and Western India (1%) (Aggarwal et al., ; Vrabelova, Letocha, Borsky, & Kozak, ), p.(Trp1153Arg), present in the European population (Waldenström, Lagerkvist, Dahlman, Westermark, & Landegren, ), is the first time being reported from India in this study. The missense mutation, p.(Ala1003Thr) (3%) and the frameshift mutation exclusive to India, p.(Thr1050Hisfs*71) (1%), affected similar proportions of patients in this study to that of previously reported studies (Aggarwal et al., ; Gupta et al., ; Kumar et al., ), indicating their overall low frequency in India.…”

“…The p.(His1069Gln), the most common mutation in European pedigree affecting 30–70% WD population, is absent in the Indian population (Gomes et al., ; Kumar et al., ). The p.(Cys271*) mutation has been reported to affect 11–20% WD population in India (Aggarwal et al., ; Gupta et al., ; Santhosh et al., ). In agreement with earlier studies, our investigation too revealed a 10% frequency of p.(Cys271*) in this region of India, which indicates that it is a common mutation in India and can be screened first in Indian WD patients.…”

“…Phenotypes associated with WD also vary, e.g., the c.3207C>A, p.(His1069Gln) mutation is common among the European population and associated with neurological manifestations, while c.2333G>T, p.(Arg778Leu) is common among Asian Population and is associated with hepatic manifestations, however, both mutations are not found in Indian population (Gomes et al., ; Kumar, Thapa, Kaur, & Prasad, ). Similarly, c.813C>A, p.(Cys271*) nonsense mutation is widely distributed in the Indian population, but it is not prevalent in western countries (Aggarwal et al., ). Except for p.(Cys271*), no other major mutations can be associated with the Indian population, as the distribution of mutations varies among WD population from different regions of India.…”

The Effect of Zinc and D-Penicillamine in a Stable Human Hepatoma ATP7B Knockout Cell Line

“…PCR products were cloned into plasmid pCR2.1-TOPO (TOPO TA Cloning kit; Invitrogen). For sequence determination of ATP7B established protocols were used [19].…”

Movement disorders: Indian scenario: A clinico-genetic review

“…The Cys271Stop was the most common mutation observed in Western India with an allelic frequency of 20.2%. [77] It was observed from four population of India that the missense mutations account for 44% of the total mutations followed by insertion and deletion mutations.…”