Analysis of clinical symptoms and ABCC6 mutations in 76 Japanese patients with pseudoxanthoma elasticum

Abstract

Pseudoxanthoma elasticum (PXE) is a hereditary disease, causing calcification and degeneration of elastic fibers, which affects the skin, eye, cardiovascular systems and gastrointestinal tract. PXE is caused by mutations in the ABCC6 gene. Neither detailed nor large-scale analyses have been accomplished in Japanese patients with PXE. We, therefore, investigated clinical symptoms and ABCC6 gene mutations in 76 Japanese patients. Japanese PXE patients (n = 76) had a significantly lower incidence of vascular lesions than 505 PXE patients in the Leiden Open Variation Database (LOVD) (38.7% vs 65.1%, respectively; P = 1.34E-06); however, the incidences of the skin, eye, cardiac and gastrointestinal lesion symptoms were not significantly different. Symptom severity scores for skin, eye and vascular lesions, calculated using the Phenodex™ system, were significantly lower in Japanese PXE patients than in LOVD PXE patients. Genetic analysis revealed three nonsense, four frame-shift, one exon deletion and 13 missense mutations in ABCC6 in 73 patients; however, we were unable to detect pathogenic mutations in three patients. Frequent mutations differed between Japanese and LOVD PXE patients. In Japanese PXE patients, the top five mutations accounted for more than 60% of all pathogenic changes, suggesting the presence of founder effects. Consistent with previous reports, no obvious correlations between genotypes and phenotypes were identified in this study. In conclusion, we consider that the milder clinical phenotypes, observed even in older Japanese PXE patients, could be attributed to environmental factors such as dietary habits and lifestyle, as well as genetic background.

ABCC6 Gene Analysis in 20 Japanese Patients with Angioid Streaks Revealing Four Frequent and Two Novel Variants and Pseudodominant Inheritance

“…Our results showed high frequencies for some variants, including 14/40 alleles (35.0%) for p.V848CfsX83, 7/40 alleles (17.5%) for p.Q378X, 6/40 alleles (15.0%) for p.R1357W, and 4/40 alleles (10.0%) for p.R419Q ( Table 2 ); of note, high frequencies for p.Q378X and p.R1357W were not found in the previous study [ 13 ]. Recently, Iwanaga et al [ 14 ] reported an ABCC6 mutation analysis study in 76 Japanese patients with PXE revealing that 56 (80%) of 76 patients had eye complications that were likely attributed to AS, while our study showed that PXE was seen in 15 of 17 AS patients (88.2%) who underwent dermatological examination. The pathogenic variant spectrum revealed five frequent variants: p.V848CfsX83 (34/152 alleles, 22.4%), p.Q378X (30/152 alleles, 19.7%), the deletion of exons 2 and 4 (15/152 alleles, 9.9%), p.Q199X (11/152 alleles, 7.2%), and p.R419Q (9/152 alleles, 5.9%) [ 14 ].…”

“…In the Japanese population, there are two case reports of ABCC6 gene analysis in patients with PXE/A [ 11 , 12 ]. Subsequently, two large-scale studies for ABCC6 gene analysis have been reported in 54 patients with AS [ 13 ] and in 76 patients with PXE [ 14 ] and have revealed differences in the ABCC6 mutation/variant spectrum between the two studies in Japanese patients [ 13 , 14 ]. For example, although the p.Q378X variant was frequently seen in PXE patients [ 14 ], it was never detected in AS patients [ 13 ].…”

“…Subsequently, two large-scale studies for ABCC6 gene analysis have been reported in 54 patients with AS [ 13 ] and in 76 patients with PXE [ 14 ] and have revealed differences in the ABCC6 mutation/variant spectrum between the two studies in Japanese patients [ 13 , 14 ]. For example, although the p.Q378X variant was frequently seen in PXE patients [ 14 ], it was never detected in AS patients [ 13 ]. In addition, two variants (p.V848CfsX83 and p.Q378X) are frequently found in PXE patients [ 14 ], leading to the hypothesis that frequently found variants may also exist in Japanese patients with AS.…”

“…For example, although the p.Q378X variant was frequently seen in PXE patients [ 14 ], it was never detected in AS patients [ 13 ]. In addition, two variants (p.V848CfsX83 and p.Q378X) are frequently found in PXE patients [ 14 ], leading to the hypothesis that frequently found variants may also exist in Japanese patients with AS.…”

First‐genetic analysis of atypical phenotype of pseudoxanthoma elasticum with ocular manifestations in the absence of characteristic skin lesions

“…Our previous report revealed that c.2542delG might not regulate the severity of skin lesions independently. 10 These findings lead to the possibility that c. 2542delG might be involved in the absence of skin lesions together with other modifying factors.…”