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 - Funding Information:
First, we thank the patients and families for their participation and consent to publish this work. Help from the following was greatly appreciated: Radiologist Marit Herder (MRI descriptions). Neurologist Synnøve Jensen (neurological examinations), geneticists Ragnhild Glad and Valeria Marton (initial evaluation and diagnostics in the two families). Cardiologists Assami Rösner and Eivind Øygard Fosse (discussion of cardiac features), ENT specialist Dagny Hemmingsen (hearing evaluation), the National Neuromuscular Center, Tromsø, Norway. We acknowledge the support from the E-Rare Joint Transnational Cantú Treat program (I-2101-B26), and NIH grant HL140024 (to CGN). Partial support for the behavioral work was provided by the Intellectual and Developmental Disabilities Research Center at Washington University (NIH/NICHD U54 HD087011; DFW). C.Mc. is supported by American Heart Association Fellowship (19POST34380407).
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 -