*4.1. ABCC6*

Over 400 mutations (https://www.ncbi.nlm.nih.gov/clinvar, accessed on 3 February 2021) have now been identified in *ABCC6*. Most of these are single nucleotide changes leading to a panel of missense, nonsense, splice site, and frameshift mutations, in addition to small and large insertions/deletions. Missense variants are found in areas critical to the stability and/or the function of the protein. Based on a small but representative number of ABCC6 mutants, two possible molecular consequences to *ABCC6* mutations were described: (1) transport deficiency linked to the failure to hydrolyze ATP and (2) abnormal protein folding leading to intracellular retention and/or reduced trafficking. The latter has been the focus of studies designed to rescue trafficking by re-purposing the drug 4-phenylbutyrate (*Cf.* Section 6.3.2). Transport deficiency and abnormal trafficking are likely the reasons behind the loss of physiological function and provide a reasonable explanation for the lack of phenotype–genotype correlation in PXE [86–88].

About 40% of all *ABCC6* gene mutations in patients with PXE consist of premature termination codon mutations and account for 25% of all mutations in PXE patients [88]. However, two mutations are recurrent in the Caucasian population, p.R1141X and g.del23- 29, which account for up to ~45% of all mutant alleles [87,88].

These ABCC6 mutations have consequences for the entire calcification pathway, as evidenced by the downregulation of ENPP1 and NT5E gene expression in the absence of ABCC6 [11,18], the reduced plasma levels of PPi [8], and the activation of TNAP as a consequence of lowered adenosine production [11,20].
