ABCC6 – Autosomal Recessive Inherited Pseudoxanthoma Elasticum

ABCC6 encodes a liver‐expressed ATP‐binding cassette transporter whose biallelic loss‐of‐function mutations underlie autosomal recessive inherited pseudoxanthoma elasticum (PXE), a systemic disorder of ectopic mineralization affecting skin, eyes, and the cardiovascular system. PXE manifests with yellow papules, dermal elastic fiber fragmentation, angioid streaks, and accelerated vascular calcification. The gene–disease relationship is supported by abundant clinical, familial, and experimental data demonstrating concordant genotype and phenotype across multiple populations.

Genetic evidence indicates an autosomal recessive inheritance pattern, with over 122 unrelated probands harboring two pathogenic ABCC6 variants (PMID:11536079). Founder alleles include the nonsense variant c.3421C>T (p.Arg1141Ter) and the recurrent exon 23–29 deletion, collectively accounting for ~30% of mutant alleles in European cohorts (PMID:11536079). Segregation analyses in 239 families revealed complete cosegregation of biallelic ABCC6 mutations with disease manifestations, confirming high penetrance in homozygotes.

Functional assays demonstrate that PXE‐associated missense and truncating variants abolish MgATP‐dependent transport of glutathione conjugates by ABCC6, without affecting ATP binding (PMID:11880368). Abcc6 knockout mice recapitulate ectopic mineralization and exhibit increased myocardial infarct size and apoptosis after ischemia–reperfusion, which is rescued by transgenic ABCC6 expression, confirming a causal role in vascular protection (PMID:21979437).

Phenotypic variability spans early‐onset generalized arterial calcification of infancy to late‐onset ocular‐limited PXE, but carriers of single ABCC6 mutations rarely develop full‐blown PXE, suggesting recessive inheritance with occasional hypomorphic allele effects (PMID:15837081). No compelling evidence disputes the gene–disease relationship.

Overall, the association between ABCC6 and autosomal recessive inherited pseudoxanthoma elasticum meets the ClinGen Definitive classification, supported by strong genetic (>122 probands; familial segregation) and functional (transport assays; animal models) evidence. Early molecular diagnosis enables timely ophthalmologic and cardiovascular surveillance, informs family counseling, and guides potential allele‐specific therapies.

Key Take-home: Biallelic ABCC6 variants cause definitive PXE, and genetic testing is clinically actionable for diagnosis, management, and family planning.

References

• American Journal of Human Genetics • 2001 • A spectrum of ABCC6 mutations is responsible for pseudoxanthoma elasticum. PMID:11536079
• The Journal of Biological Chemistry • 2002 • Loss of ATP-dependent transport activity in pseudoxanthoma elasticum-associated mutants of human ABCC6 (MRP6). PMID:11880368
• Arteriosclerosis, Thrombosis, and Vascular Biology • 2011 • Abcc6 deficiency causes increased infarct size and apoptosis in a mouse cardiac ischemia-reperfusion model. PMID:21979437
• International Journal of Cardiology • 2005 • Patients with premature coronary artery disease who carry the ABCC6 R1141X mutation have no Pseudoxanthoma Elasticum phenotype. PMID:15837081

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