Cantú syndrome resulting from activating mutation in the KCNJ8 gene.
ATP-sensitive potassium (KATP ) channels, composed of inward-rectifying potassium channel subunits (Kir6.1 and Kir6.2, encoded by KCNJ8 and KCNJ11, respectively) and regulatory sulfonylurea receptor (SUR1 and SUR2, encoded by ABCC8 and ABCC9, respectively), couple metabolism to excitability in multiple tissues. Mutations in ABCC9 cause Cantú syndrome (CS), a distinct multiorgan disease, potentially via enhanced KATP channel activity. We screened KCNJ8 in an ABCC9 mutation-negative patient who also exhibited clinical hallmarks of CS (hypertrichosis, macrosomia, macrocephaly, coarse facial appearance, cardiomegaly, and skeletal abnormalities). We identified a de novo missense mutation encoding Kir6.1[p.Cys176Ser] in the patient. Kir6.1[p.Cys176Ser] channels exhibited markedly higher activity than wild-type channels, as a result of reduced ATP sensitivity, whether coexpressed with SUR1 or SUR2A subunits. Our results identify a novel causal gene in CS, but also demonstrate that the cardinal features of the disease result from gain of KATP channel function, not from a Kir6-independent SUR2 function.
Department of Cell Biology and Physiology, and Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St. Louis, Missouri.
Paige E
PE
Cooper
Heiko
H
Reutter
Joachim
J
Woelfle
Hartmut
H
Engels
Dorothy K
DK
Grange
Gijs
G
van Haaften
Bregje W
BW
van Bon
Alexander
A
Hoischen
Colin G
CG
Nichols
D000293:Adolescent; D006332:Cardiomegaly / Q000175:diagnosis / Q000235:genetics*; D004252:DNA Mutational Analysis; D019066:Facies; D040181:Genetic Diseases, X-Linked / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D006983:Hypertrichosis / Q000175:diagnosis / Q000235:genetics*; D054086:KATP Channels / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials; D008958:Models, Molecular; D009154:Mutation; D020125:Mutation, Missense; D010009:Osteochondrodysplasias / Q000175:diagnosis / Q000235:genetics*; D010641:Phenotype; D011487:Protein Conformation
D054086:KATP Channels; C092520:uK-ATP-1 potassium channel
Cantú syndrome; KATP; KCNJ8; Kir6.1; hypertrichosis