Cantu Syndrome (CS) is a complex disorder caused by gain-of-function (GoF) mutations in ABCC9 and KCNJ8, which encode the SUR2 and Kir6.1 subunits, respectively, of vascular smooth muscle (VSM) KATP channels.
Cantú syndrome (CS), first described in 1982, is caused by pathogenic variants in ABCC9 and KCNJ8, which encode the regulatory and pore forming subunits of ATP-sensitive potassium (K<sub>ATP</sub> ) channels, respectively.
Cantu syndrome-associated SUR2 (ABCC9) mutations in distinct structural domains result in K<sub>ATP</sub> channel gain-of-function by differential mechanisms.
Three of these lines carry gain-of-function mutations in genes encoding the pore-forming (Kir6.1, <i>KCNJ8</i>) and regulatory (SUR2, <i>ABCC9</i>) subunits of an ATP-sensitive potassium channel (K<sub>ATP</sub>) linked to Cantú syndrome (CS).
To investigate pathophysiologic mechanisms in CS we have used CRISPR/Cas9 engineering to introduce CS-associated SUR2[A478V] and Kir6.1[V65M] mutations to the equivalent endogenous loci in mice.
Conserved functional consequences of disease-associated mutations in the slide helix of Kir6.1 and Kir6.2 subunits of the ATP-sensitive potassium channel.
The patient reported here gives further evidence that these syndromes are an expression of the ABCC9-related disorders, ranging from hypertrichosis and acromegaloid facies to the severe end of Cantu syndrome.
Gain-of-function (GOF) mutations in the KATP channel subunits Kir6.1 and SUR2 cause Cantu syndrome (CS), a disease characterized by multiple cardiovascular abnormalities.
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).
Therefore, we propose that ABCC9 mutations lead to a spectrum of phenotypes formerly known as Cantú syndrome, HAFF and AFA, which may not be clearly distinguishable by clinical criteria, and that all patients with clinical signs belonging to this spectrum should be revisited and offered ABCC9 mutation analysis.