ABCC9-related Intellectual disability Myopathy Syndrome is a KATP channelopathy with loss-of-function mutations in ABCC9

Marie F Smeland; Conor McClenaghan; Helen I Roessler; Sanne Savelberg; Geir Åsmund Myge Hansen; Helene Hjellnes; Kjell Arne Arntzen; Kai Ivar Müller; Andreas Rosenberger Dybesland; Theresa Harter; Monica Sala-Rabanal; Chris H Emfinger; Yan Huang; Soma S Singareddy; Jamie Gunn; David F Wozniak; Attila Kovacs; Maarten Massink; Federico Tessadori; Sarah M Kamel; Jeroen Bakkers; Maria S Remedi; Marijke Van Ghelue; Colin G Nichols; Gijs van Haaften

doi:10.1038/s41467-019-12428-7

ABCC9-related Intellectual disability Myopathy Syndrome is a K_ATP channelopathy with loss-of-function mutations in ABCC9

Nat Commun. 2019 Oct 1;10(1):4457. doi: 10.1038/s41467-019-12428-7.

Authors

Marie F Smeland¹, Conor McClenaghan², Helen I Roessler³, Sanne Savelberg³, Geir Åsmund Myge Hansen⁴, Helene Hjellnes⁴, Kjell Arne Arntzen^{5

6

7}, Kai Ivar Müller^{5

6}, Andreas Rosenberger Dybesland^{7

8}, Theresa Harter², Monica Sala-Rabanal^{2

9}, Chris H Emfinger², Yan Huang^{2

10}, Soma S Singareddy², Jamie Gunn¹¹, David F Wozniak¹¹, Attila Kovacs¹², Maarten Massink³, Federico Tessadori^{3

13}, Sarah M Kamel¹³, Jeroen Bakkers^{13

14}, Maria S Remedi¹⁵, Marijke Van Ghelue^{4

16}, Colin G Nichols², Gijs van Haaften¹⁷

Affiliations

¹ Department of Medical Genetics, University Hospital of North Norway, 9019, Tromsø, Norway. [email protected].
² Department of Cell Biology and Physiology, and Center for the Investigation of Membrane Excitability Diseases (CIMED), Washington University, St Louis, MO, 63110, USA.
³ Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, 3584 CX, Utrecht, the Netherlands.
⁴ Department of Medical Genetics, University Hospital of North Norway, 9019, Tromsø, Norway.
⁵ Department of Neurology, University Hospital of North Norway, 9019, Tromsø, Norway.
⁶ Department of Clinical Medicine, UiT-The Arctic University of Norway, 9019, Tromsø, Norway.
⁷ The National Neuromuscular Centre of Norway, University Hospital of North Norway, 9019, Tromsø, Norway.
⁸ Department of Physiotherapy, University Hospital of North Norway, 9019, Tromsø, Norway.
⁹ Department of Anesthesiology, Washington University, St Louis, MO, 63110, USA.
¹⁰ Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.
¹¹ Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, 63110, USA.
¹² Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA.
¹³ Hubrecht Institute-KNAW and UMC Utrecht, 3584 CT, Utrecht, the Netherlands.
¹⁴ Department of Medical Physiology, Division of Heart and Lungs, University Medical Center Utrecht, 3584 CX, Utrecht, the Netherlands.
¹⁵ Department of Medicine, Division of Endocrinology, Metabolism and Lipid Research, Washington University, St Louis, MO, 63110, USA.
¹⁶ Department of Medical Genetics, the Arctic University of Norway, 9019, Tromsø, Norway.
¹⁷ Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, 3584 CX, Utrecht, the Netherlands. [email protected].

Abstract

Mutations in genes encoding K_ATP 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 K_ATP channels. This mutation results in an in-frame deletion of exon 8, which results in non-functional K_ATP 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 K_ATP 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 K_ATP loss- versus gain-of-function.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adenosine Triphosphate / metabolism*
Adolescent
Adult
Amino Acid Sequence
Animals
Cardiomegaly / genetics
Cardiomegaly / metabolism
Cell Line
Channelopathies / metabolism*
Child
Disease Models, Animal
Facies
Female
Genetic Diseases, X-Linked / genetics
Genetic Predisposition to Disease / genetics*
Heart
Heart Diseases / genetics
Heart Diseases / metabolism
Homozygote
Humans
Hypertrichosis / genetics
Hypertrichosis / metabolism
Intellectual Disability / metabolism*
Intellectual Disability / parasitology
Male
Mediator Complex / metabolism
Membrane Proteins / metabolism
Mice
Muscular Diseases / genetics
Muscular Diseases / metabolism*
Mutation*
Neurodevelopmental Disorders / genetics
Neurodevelopmental Disorders / metabolism
Neurodevelopmental Disorders / physiopathology
Osteochondrodysplasias / genetics
Osteochondrodysplasias / metabolism
Pedigree
Phenotype
Rubidium
Sulfonylurea Receptors / genetics*
Sulfonylurea Receptors / metabolism*
Whole Genome Sequencing
Young Adult
Zebrafish

Substances

ABCC9 protein, human
MED23 protein, human
Mediator Complex
Membrane Proteins
Sulfonylurea Receptors
Adenosine Triphosphate
Rubidium

Supplementary concepts

Cantu syndrome

Abstract

Publication types

MeSH terms

Substances

Supplementary concepts

Grants and funding