The pathogenic p.R391G ABCC6 displays incomplete penetrance implying the necessity of an interacting partner for the development of pseudoxanthoma elasticum

Abstract

ABCC6 encodes a transmembrane transporter playing a primary role in the efflux of ATP from hepatocytes to the bloodstream. ATP is then cleaved to AMP and inorganic pyrophosphate, a major inhibitor of ectopic calcification. Pathogenic variants of ABCC6 cause pseudoxanthoma elasticum, a multisystemic recessive ectopic calcification disease of variable severity. One of the mechanisms influencing the heterogeneity of a disorder is the penetrance of pathogenic variants. The penetrance of a sequence variant shows the proportion of individuals developing the expected phenotype in the presence of the variant. Incomplete penetrance indicates that the disease does not develop in all the cases when the pathogenic variant is present. Here, we investigated whether incomplete penetrance participates in the heterogeneity of pseudoxanthoma elasticum. By integrating the clinical and genetic data of 590 patients, we created the largest European pseudoxanthoma elasticum cohort. We identified two incomplete penetrant pathogenic variants, p.(V787I) and p.(R391G), based on their allele frequencies in our cohort and in the European reference population of gnomAD. The detailed characterization of the frequent p.(R391G) pathogenic variant suggested only 2% penetrance with an unaltered severity of the clinical phenotype. Based on our biochemical analysis, we hypothesize that the variant becomes deleterious only if an interacting partner is mutated simultaneously. These data point to new molecular mechanisms by revealing the potential existence of the first interacting partner of ABCC6. Our data are important for genetic counseling of pseudoxanthoma elasticum, suggesting a much lower disease heritability of these pathogenic variants.

Clinical Characterization of Korean Patients with Pseudoxanthoma Elasticum and Angioid Streaks

“…This indicates the presence of a shared genetic background among East Asian patients with PXE. There is an ethnic difference in the prevalence of ABCC6 variants in European patients with PXE; the frequent variant of p.Arg1141Ter accounts for 1/3 of all mutations in this population [36]. Further studies with large sample sizes are required to identify ethnicity-specific variants in East Asians.…”

Correlation of systemic involvement and presence of pathological skin calcification assessed by ex vivo nonlinear microscopy in Pseudoxanthoma elasticum

“…The attempts to give insights into the natural history of PXE are still ongoing, but the number of studies that address this question is scarce [30]. Objective evaluation of the severity of PXE is challenging, although different methods were used to investigate the relationship between cutaneous and systemic involvement [18,27,31,32].…”

Connecting the Dots of a Rare Connective Tissue Disease: Pseudoxanthoma Elasticum

“…It is an autosomal recessive condition with a molecular mutation in the ABCC6 gene, located on the short arm of chromosome 16 [ 3 ]. It demonstrates incomplete penetrance where the estimated incidence is approximately one in 25,000 to 100,000 people, with women accounting for two-thirds of cases [ 2 , 4 , 5 ]. PXE typically presents as xanthomatous skin lesions, which should indicate a skin biopsy with genetic testing, if needed [ 1 , 2 ].…”