ABCC9 – Cantu Syndrome

Cantu syndrome (hypertrichotic osteochondrodysplasia Cantu type) is an autosomal dominant multisystem disorder characterized by congenital hypertrichosis, coarse facial features, osteochondrodysplasia and variable cardiovascular anomalies, most commonly cardiomegaly. The syndrome is caused by gain-of-function missense variants in ABCC9, which encodes the SUR2 subunit of ATP-sensitive potassium (KATP) channels predominantly expressed in cardiac, skeletal, and smooth muscle (PMID:22608503, PMID:22610116).

Genetic studies include exome sequencing in 16 simplex and familial cases, identifying 11 distinct ABCC9 missense mutations with recurrent involvement of residue Arg1154 (e.g., c.3461G>A (p.Arg1154Gln) and c.3460C>T (p.Arg1154Trp)) and a total of >=31 molecularly confirmed subjects (PMID:22608503, PMID:36515236). Many variants are de novo, with additional segregation in multiplex pedigrees including a Japanese father–son pair and a three-generation kindred of five affected individuals (PMID:24352916, PMID:29327300).

Segregation analysis across these families shows at least 11 affected relatives harboring ABCC9 variants co-segregating with the phenotype, reinforcing dominant inheritance and high penetrance (PMID:24352916, PMID:39031464). The most frequently reported variant, c.3605C>T (p.Thr1202Met), has been observed in multiple unrelated probands.

Functional assays demonstrate that Cantu syndrome–associated SUR2 mutations reduce ATP-mediated channel inhibition and/or enhance MgADP activation, leading to KATP gain-of-function. Electrophysiological recordings in heterologous systems and native cells confirm decreased sensitivity to inhibitory ATP concentrations and augmented channel opening for p.Thr1202Met and p.Arg1154Gln (PMID:22610116, PMID:29275331).

Further studies evaluate drug sensitivity, showing most SUR2 mutants remain inhibitable by sulfonylureas (e.g., glibenclamide), suggesting potential therapeutic avenues to mitigate hyperactive KATP currents. Structural and splicing analyses also reveal variant-specific impacts on channel assembly and ankyrin B interactions.

Clinically, ABCC9 testing enables definitive diagnosis, guides cardiovascular surveillance (echocardiography, vascular imaging), and informs targeted management. Key take-home: genetic confirmation of ABCC9 gain-of-function variants provides definitive diagnosis and supports use of SUR2 antagonists in Cantu syndrome.

References

• American Journal of Human Genetics • 2012 • Cantú syndrome is caused by mutations in ABCC9 PMID:22608503
• Nature Genetics • 2012 • Dominant missense mutations in ABCC9 cause Cantú syndrome PMID:22610116
• American Journal of Medical Genetics Part A • 2014 • Aortic aneurysm and craniosynostosis in a family with Cantu syndrome. PMID:24352916
• Journal of the American Heart Association • 2022 • A Unique High-Output Cardiac Hypertrophy Phenotype Arising From Low Systemic Vascular Resistance in Cantu Syndrome. PMID:36515236
• The Journal of Biological Chemistry • 2018 • Cantu syndrome-associated SUR2 (ABCC9) mutations in distinct structural domains result in KATP channel gain-of-function by differential mechanisms. PMID:29275331

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