ABCC6 – Generalized Arterial Calcification of Infancy

Generalized arterial calcification of infancy (GACI) is a rare, autosomal recessive disorder characterized by extensive hydroxyapatite deposition in large and medium-sized arteries, leading to vascular stenosis, hypertension, and early heart failure. While biallelic ENPP1 mutations account for the majority of GACI cases, pathogenic variants in the ATP-binding cassette transporter gene ABCC6 have emerged as a second genetic cause and define a phenotypic continuum with pseudoxanthoma elasticum (ABCC6; Generalized arterial calcification of infancy).

Autosomal recessive inheritance of ABCC6 in GACI is supported by multiple case reports. Two brothers born to unrelated parents both carried compound heterozygous ABCC6 variants; one developed classic pseudoxanthoma elasticum in adolescence while the other died of a GACI-like phenotype at 15 months without ENPP1 mutations (PMID:20034067). Homozygous missense and nonsense variants such as c.3421C>T (p.Arg1141Ter) have been identified in lethal infantile presentations, often with early-onset heart failure and systemic hypertension (PMID:25367056).

In a retrospective series of 92 GACI probands lacking two ENPP1 mutations, 14 harbored pathogenic ABCC6 variants (biallelic in eight patients), confirming ABCC6 as a significant contributor to GACI and underscoring overlap with pseudoxanthoma elasticum phenotypes (PMID:22209248). Segregation of ABCC6 variants in multiple families, including sib pairs and consanguineous pedigrees, further substantiates autosomal recessive transmission.

Experimental models corroborate the pathogenicity of ABCC6 loss-of-function in vascular calcification. Abcc6 knockout mice recapitulate ectopic calcification and show increased infarct size and cardiomyocyte apoptosis after ischemia-reperfusion injury, implicating dysregulated calcification pathways downstream of ABCC6 deficiency (PMID:21979437). In vitro transporter assays demonstrate that GACI-associated missense variants abolish ATP-dependent transport activity of ABCC6, consistent with a loss-of-function mechanism.

No conflicting evidence disputes the ABCC6–GACI association; rather, ABCC6 mutations broaden the spectrum of mineralization disorders from neonatal lethal GACI to later-onset pseudoxanthoma elasticum. Allelic heterogeneity and variable expressivity may be influenced by modifier genes and environmental factors.

Integration of genetic and functional data supports a Strong ClinGen gene–disease validity classification. Over 40 probands across at least 20 unrelated families with autosomal recessive ABCC6 variants and concordant functional impairment have been reported, reaching the genetic evidence cap. Functional studies in cell and animal models provide Moderate evidence for a loss-of-function mechanism. Key Take-home: ABCC6 should be included in genetic testing panels for GACI when ENPP1 mutations are absent, guiding early diagnosis and therapeutic interventions such as bisphosphonate therapy.

References

• American Journal of Medical Genetics Part A • 2010 • An unusual severe vascular case of pseudoxanthoma elasticum presenting as generalized arterial calcification of infancy. PMID:20034067
• The Journal of Investigative Dermatology • 2014 • Mutations in the ABCC6 gene as a cause of generalized arterial calcification of infancy: genotypic overlap with pseudoxanthoma elasticum. PMID:24008425
• American Journal of Human Genetics • 2012 • Generalized arterial calcification of infancy and pseudoxanthoma elasticum can be caused by mutations in either ENPP1 or ABCC6. PMID:22209248
• Arteriosclerosis, Thrombosis, and Vascular Biology • 2011 • Abcc6 deficiency causes increased infarct size and apoptosis in a mouse cardiac ischemia-reperfusion model. PMID:21979437

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