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.

Figure 1

Mutations in ABCC9 Cause Cantú Syndorme (A) Portrait photographs of Cantú syndrome individuals with ABCC9 mutations, identified by exome sequencing or Sanger sequencing. Note the coarse facial appearance, including a broad nasal bridge, a short nose, a long philtrum, a wide mouth, and full lips. (B) De novo ABCC9 mutation g.21995261G>A (c.3460C>T; p. Arg1154Trp) identified by exome sequencing of an affected individual and his parents. The upper panel shows the next generation sequencing reads of the child (individual 1) followed by the reads of the father (middle) and mother (bottom). (C) Sanger validation in the same trio; Sanger traces of the child (individual 1, top), father (middle), and mother (bottom). The point mutation (g.21995261G>A; c.3460C>T) is marked with a red arrow. (D) Schematic overview of SUR2, with Cantú syndrome-causing mutations depicted by the arrow. Abbreviations: ABC, ATP-binding cassette transporter domain (red); TMD, ABC transmembrane domain type-1 (blue). (E) Amino-acid conservation of the mutation hot spot p.Arg1154 for multiple species (human, mouse, dog, chicken, zebrafish); the highly conserved arginine is depicted in red.