TY - JOUR
T1 - ABCC9-related Intellectual disability Myopathy Syndrome is a KATP channelopathy with loss-of-function mutations in ABCC9
AU - Smeland, Marie F.
AU - McClenaghan, Conor
AU - Roessler, Helen I.
AU - Savelberg, Sanne
AU - Hansen, Geir Åsmund Myge
AU - Hjellnes, Helene
AU - Arntzen, Kjell Arne
AU - Müller, Kai Ivar
AU - Dybesland, Andreas Rosenberger
AU - Harter, Theresa
AU - Sala-Rabanal, Monica
AU - Emfinger, Chris H.
AU - Huang, Yan
AU - Singareddy, Soma S.
AU - Gunn, Jamie
AU - Wozniak, David F.
AU - Kovacs, Attila
AU - Massink, Maarten
AU - Tessadori, Federico
AU - Kamel, Sarah M.
AU - Bakkers, Jeroen
AU - Remedi, Maria S.
AU - Van Ghelue, Marijke
AU - Nichols, Colin G.
AU - van Haaften, Gijs
N1 - Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - Mutations in genes encoding KATP channel subunits have been reported for pancreatic disorders and Cantú syndrome. Here, we report a syndrome in six patients from two families with a consistent phenotype of mild intellectual disability, similar facies, myopathy, and cerebral white matter hyperintensities, with cardiac systolic dysfunction present in the two oldest patients. Patients are homozygous for a splice-site mutation in ABCC9 (c.1320 + 1 G > A), which encodes the sulfonylurea receptor 2 (SUR2) subunit of KATP channels. This mutation results in an in-frame deletion of exon 8, which results in non-functional KATP channels in recombinant assays. SUR2 loss-of-function causes fatigability and cardiac dysfunction in mice, and reduced activity, cardiac dysfunction and ventricular enlargement in zebrafish. We term this channelopathy resulting from loss-of-function of SUR2-containing KATP channels ABCC9-related Intellectual disability Myopathy Syndrome (AIMS). The phenotype differs from Cantú syndrome, which is caused by gain-of-function ABCC9 mutations, reflecting the opposing consequences of KATP loss- versus gain-of-function.
AB - Mutations in genes encoding KATP channel subunits have been reported for pancreatic disorders and Cantú syndrome. Here, we report a syndrome in six patients from two families with a consistent phenotype of mild intellectual disability, similar facies, myopathy, and cerebral white matter hyperintensities, with cardiac systolic dysfunction present in the two oldest patients. Patients are homozygous for a splice-site mutation in ABCC9 (c.1320 + 1 G > A), which encodes the sulfonylurea receptor 2 (SUR2) subunit of KATP channels. This mutation results in an in-frame deletion of exon 8, which results in non-functional KATP channels in recombinant assays. SUR2 loss-of-function causes fatigability and cardiac dysfunction in mice, and reduced activity, cardiac dysfunction and ventricular enlargement in zebrafish. We term this channelopathy resulting from loss-of-function of SUR2-containing KATP channels ABCC9-related Intellectual disability Myopathy Syndrome (AIMS). The phenotype differs from Cantú syndrome, which is caused by gain-of-function ABCC9 mutations, reflecting the opposing consequences of KATP loss- versus gain-of-function.
UR - http://www.scopus.com/inward/record.url?scp=85072847290&partnerID=8YFLogxK
U2 - 10.1038/s41467-019-12428-7
DO - 10.1038/s41467-019-12428-7
M3 - Article
C2 - 31575858
AN - SCOPUS:85072847290
SN - 2041-1723
VL - 10
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 4457
ER -