Mutation of KCNJ8 in a patient with Cantú syndrome with unique vascular abnormalities - support for the role of K(ATP) channels in this condition

Abstract

KCNJ8 (NM_004982) encodes the pore forming subunit of one of the ATP-sensitive inwardly rectifying potassium (KATP) channels. KCNJ8 sequence variations are traditionally associated with J-wave syndromes, involving ventricular fibrillation and sudden cardiac death. Recently, the KATP gene ABCC9 (SUR2, NM_020297) has been associated with the multi-organ disorder Cantú syndrome or hypertrichotic osteochondrodysplasia (MIM 239850) (hypertrichosis, macrosomia, osteochondrodysplasia, and cardiomegaly). Here, we report on a patient with a de novo nonsynonymous KCNJ8 SNV (p.V65M) and Cantú syndrome, who tested negative for mutations in ABCC9. The genotype and multi-organ abnormalities of this patient are reviewed. A careful screening of the KATP genes should be performed in all individuals diagnosed with Cantú syndrome and no mutation in ABCC9.

Keywords: Cantú syndrome; Exome; Mutation; Potassium channel.

Figure 1

Clinical phenotype of the patient. Shown are photographs of the patient, (A-B) when an infant, (A) face and right arm, (B) his back, and (C-E) his recent pictures (C) his face, (D) palm and (E) sole. His (F-K) MRI imaging of the brain at 8 months of age is also shown, specifically, (F) axial T-2 weighted, (G) sagittal T-1 weighted, (H-I), MR angiography, and (J-K) MR venography. Note the hypertrichosis, short neck (A-B) and coarse facial features including bulbous nose, prominent mouth, thick lips and gingival hyperplasia with irregular teeth (C). Deep palmar and plantar creases with wrinkled skin and thickened pads on palms and soles are also seen (D-E). MRI findings include cerebral atrophy (F-G), thick calvarium (G), thin corpus callosum (G), tortuous circle of Willis (H) and internal carotids (I), multiple tortuous venous collaterals and no flow in the inferior saggital sinus.

Figure 2

KCNJ8 p.V65M mutation in the proband with Cantú syndrome. A) Sanger DNA sequencing of genomic PCR products confirms a de novo c.193G>A transition mutation in the proband (P), that is absent in the mother (M) and father (F) below. B) Schematic of a single Kir6.1 subunit oriented in the plasma membrane illustrating the cytoplasmic amino (N) and carboxy (C) terminal domains responsible for subunit association. The two transmembrane domains encoded by residues 70-94 and 155-176 are shown as cylinders with the selectivity filter (residues 140-145) in between. Location of the p.V65M mutation is indicated with a red arrow and asterisk. C) Pileup of Kir6.1 amino acid sequences illustrating high degree of evolutionary conservation of p.V65 through mammalian, avian, amphibian and telost fish orthologues (species and Genbank sequence IDs indicated at left). The proband's mutated sequence is shown at top.