Cantú Syndrome Is Caused by Mutations in ABCC9

Abstract

Cantú syndrome is a rare disorder characterized by congenital hypertrichosis, neonatal macrosomia, a distinct osteochondrodysplasia, and cardiomegaly. Using an exome-sequencing approach applied to one proband-parent trio and three unrelated single cases, we identified heterozygous mutations in ABCC9 in all probands. With the inclusion of the remaining cohort of ten individuals with Cantú syndrome, a total of eleven mutations in ABCC9 were found. The de novo occurrence in all six simplex cases in our cohort substantiates the presence of a dominant disease mechanism. All mutations were missense, and several mutations affect Arg1154. This mutation hot spot lies within the second type 1 transmembrane region of this ATP-binding cassette transporter protein, which may suggest an activating mutation. ABCC9 encodes the sulfonylurea receptor (SUR) that forms ATP-sensitive potassium channels (K(ATP) channels) originally shown in cardiac, skeletal, and smooth muscle. Previously, loss-of-function mutations in this gene have been associated with idiopathic dilated cardiomyopathy type 10 (CMD10). These findings identify the genetic basis of Cantú syndrome and suggest that this is a new member of the potassium channelopathies.

Melanocytes and Their Diseases

“…POEMS syndrome ( polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes) is a multisystem disorder associated with plasma cell dyscrasia, and patients with POEMS syndrome show up-regulated serum levels of angiogenetic factors including VEGF (vascular endothelial growth factor) and HGF (hepatocyte growth factor) (Yamada et al 2013). Cantu syndrome, characterized by hypertrichosis, macrosomia, osteochondrodysplasia, and cardiomegaly, is reported to be caused by mutations in ABCC9 (ATP-binding cassette, subfamily C, member 9) (van Bon et al 2012). McCune-Albright syndrome results from somatic mutations of the GNAS gene (G-protein a-subunit) especially mutations in Gsa (stimulatory G protein) (Dumitrescu and Collins 2008).…”

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.…”

Cantú Syndrome Associated with Ovarian Agenesis

“…Cantú syndrome has been considered as a new member of potassium channelopathies [van Bon et al, 2012]. The syndrome has been attributed to mutated ABCC9 or KCNJ8 genes as the underlying causes.…”

“…The facial appearance resembles acromegaloid syndromes or storage disorders [Harakalova et al, 2012;van Bon et al, 2012]. To date, about 50 cases with Cantú syndrome have been reported, and heterozygous pathogenic variants in the ABCC9 or the KCNJ8 genes have been found in 80% of the cases [van Bon et al, 2012;Czeschik et al, 2013].…”

“…The facial appearance resembles acromegaloid syndromes or storage disorders [Harakalova et al, 2012;van Bon et al, 2012]. To date, about 50 cases with Cantú syndrome have been reported, and heterozygous pathogenic variants in the ABCC9 or the KCNJ8 genes have been found in 80% of the cases [van Bon et al, 2012;Czeschik et al, 2013]. Cantú syndrome is caused by gain-of-function mutations in the genes encoding the pore-forming (Kir6.1 , KCNJ8 ) and regulatory (SUR2, ABCC9 ) subunits of the predominately cardiovascular isoforms of the K ATP sensitive channel [van Bon et al, 2012].…”