High prevalence of the very rare wilson disease gene mutation Leu708Pro in the Island of Gran Canaria (Canary Islands, Spain): A genetic and clinical study

Abstract

The molecular basis of Wilson disease (WD), an autosomal recessive disorder, is the presence of mutations in the ATP7B gene, a copper transporting ATPase. Hospital records indicated a higher prevalence of WD (1 in 2,600) in some counties in the northeastern region of the island of Gran Canaria (Canary Islands, Spain) that was around 10-fold higher than that described for European populations (1 in 30,000). The ATP7B gene was analyzed for mutations in 24 affected subjects, revealing a high prevalence of the rare Leu708Pro mutation present in 12 homozygous and 7 heterozygous individuals. In these patients, who constitute one of the largest described cohorts of WD homozygotes, we found a variable clinical presentation of the disease, although the biochemical picture was homogenous and characteristic, thereby confirming that the Leu708Pro change is indeed a mutation associated with WD. Haplotype analysis of subjects homozygous for the Leu708Pro mutation showed a conserved shared region smaller than 1 centimorgan (cM), and the region of linkage disequilibrium between the Leu708Pro mutation and neighboring microsatellite markers extended approximately 4.6 cM. When comparing the amount of linkage disequilibrium versus genetic distance from the disease mutation, it was estimated that a common ancestral Leu708Pro chromosome may have been introduced in Gran Canaria over 56 generations ago, dating it back to pre-Hispanic times. The prevalence, and the tight geographical distribution of the Leu708Pro chromosome suggests that the Canary Islands can be considered a genetic isolate for linkage disequilibrium studies.

Identification of a novel Wilson disease gene mutation frequent in Upper Austria: a genetic and clinical study

“…24 In the Island of Gran Canaria, an archipelago near the northwest Atlantic coast of Africa, a high frequency of the very rare p.Leu708Pro(c.2123T4C) mutation was described, finding a total of 12 homozygous and 7 heterozygous individuals. 13 All known WD patients in Iceland carry the Y760X (c.2007_2013del, exon 7) mutation. 25 These findings reflect local founder mutations in geographically restricted areas.…”

“…9,10 In other regions, other mutations are more frequent, like in Sardinia (c. À441_ À427del), in Spain (p.Met645Arg(c.1934T4G), exon 6) or in the Canary Islands (p.Leu708(Proc.2123T4C), exon 8). [11][12][13] Most of the other mutations appear at low frequency and are associated with specific ethnic groups, or occur within single families. [14][15][16] Knowledge of the regional distribution of mutations of the WD gene is important to allow testing for the most common mutations in a population, thereby obtaining a rapid diagnosis in unclear cases, while comprehensive genetic testing will take at least several weeks currently.…”

A New Mutation of Wilson's Disease P-Type ATPase Gene in a Patient with Cirrhosis and Coombs-Positive Hemolytic Anemia

“…Clinical manifestations of WD are different and heterogeneous, also in patients carrying the same homozygous mutation (24)(25)(26). Consequently, it is hypothesized that other additional genetic and/or environmental factors could influence the phenotypes of WD.…”

Diagnostic Accuracy of Serum Ceruloplasmin in Wilson Disease: Determination of Sensitivity and Specificity by ROC Curve Analysis among ATP7B-Genotyped Subjects

“…The disease frequency is highly variable, and WD is seen more frequently in Sardinia, China, Japan, and other Asian populations (2)(3)(4)(5)(6)(7)(8)(9). Underdiagnosis of WD is highly likely, especially during the asymptomatic phase and in patients with atypical presentations.…”