Dominant missense mutations in ABCC9 cause Cantú syndrome

Abstract

Cantú syndrome is characterized by congenital hypertrichosis, distinctive facial features, osteochondrodysplasia and cardiac defects. By using family-based exome sequencing, we identified a de novo mutation in ABCC9. Subsequently, we discovered novel dominant missense mutations in ABCC9 in 14 of the 16 individuals with Cantú syndrome examined. The ABCC9 protein is part of an ATP-dependent potassium (K(ATP)) channel that couples the metabolic state of a cell with its electrical activity. All mutations altered amino acids in or close to the transmembrane domains of ABCC9. Using electrophysiological measurements, we show that mutations in ABCC9 reduce the ATP-mediated potassium channel inhibition, resulting in channel opening. Moreover, similarities between the phenotype of individuals with Cantú syndrome and side effects from the K(ATP) channel agonist minoxidil indicate that the mutations in ABCC9 result in channel opening. Given the availability of ABCC9 antagonists, our findings may have direct implications for the treatment of individuals with Cantú syndrome.

Further confirmation of the MED13L haploinsufficiency syndrome

“…Trio-based whole-exome sequencing was performed on patient 1 and parents as described previously 5 with the alterations that sequencing was performed on the Solid 5500 platform and enrichment was performed using the Agilent Sureselect kit (v4; Agilent, Santa Clara, CA, USA). The obtained average coverage was 69, 77 and 66 Â for the patient, father and mother, respectively.…”

Cantú Syndrome with panhypopituitarism

“…Individuals affected by Cantú syndrome also tend to exhibit coarse facies, similar to acromegaly in appearance. The genetic basis of Cantú syndrome was elucidated by Van bon et al and Harkalova et al in 2012, who demonstrated that mutations in the ABCC9 gene appear to be causative of Cantú syndrome [2,3]. The ABCC9 gene encodes the channel regulation protein SUR2, which acts as part of an adenosine triphosphate-sensitive potassium channel.…”

Role of KCNJ11 Gene Polymorphisms and Risk of Type 2 Diabetes Mellitus

“…Mutations in the KCNJ11 gene can cause T2DM because of the reduced ability of ATP to inhibit the activity of the KATP channel and the enhanced ability of MgATP to simultaneously stimulate the function of this channel. This is associated with defective insulin secretion, ultimately causing T2DM 28,93 .…”

“…Both proteins form compartments in the KATP channels which allow potassium to flow into the cell rather than out of it, as mediated by G proteins 28 . The KATP channel interacts with different types of VSCCs, including L (long-lasting), N (neural), P/Q (purkinje), R (residual) and T (transient).…”