2. Academic Validation
  3. Heterozygous Variants in the Mechanosensitive Ion Channel TMEM63A Result in Transient Hypomyelination during Infancy

Heterozygous Variants in the Mechanosensitive Ion Channel TMEM63A Result in Transient Hypomyelination during Infancy

  • Am J Hum Genet. 2019 Nov 7;105(5):996-1004. doi: 10.1016/j.ajhg.2019.09.011.
Huifang Yan 1,  Guy Helman 2,  Swetha E Murthy 3,  Haoran Ji 4,  Joanna Crawford 5,  Thomas Kubisiak 6,  Stephen J Bent 7,  Jiangxi Xiao 8,  Ryan J Taft 9,  Adam Coombs 3,  Ye Wu 10,  Ana Pop 11,  Dongxiao Li 12,  Linda S de Vries 13,  Yuwu Jiang 14,  Gajja S Salomons 15,  Marjo S van der Knaap 16,  Ardem Patapoutian 3,  Cas Simons 2,  Margit Burmeister 17,  Jingmin Wang 18,  Nicole I Wolf 19
Affiliations

Affiliations

  • 1 Department of Pediatrics, Beijing Key Laboratory of Molecular Diagnosis and Study on Pediatric Genetic Diseases, Peking University First Hospital, Beijing 100871, China; Molecular & Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109, USA; Joint International Research Center of Translational and Clinical Research, Beijing 100871, China.
  • 2 Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville, Melbourne, VIC 3052, Australia; Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
  • 3 Howard Hughes Medical Institute, Department of Neuroscience, Dorris Neuroscience Center, Scripps Research, La Jolla, CA 92037 USA.
  • 4 Department of Pediatrics, Beijing Key Laboratory of Molecular Diagnosis and Study on Pediatric Genetic Diseases, Peking University First Hospital, Beijing 100871, China; Children's Hospital of Zhejiang University School of Medicine, Hangzhou 310058, China.
  • 5 Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
  • 6 Molecular & Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109, USA.
  • 7 Data61, Commonwealth Scientific and Industrial Research Organisation, Brisbane, QLD 4067, Australia.
  • 8 Department of Radiology, Peking University First Hospital, Beijing 100871, China.
  • 9 Illumina, Inc., San Diego, CA 92121, USA.
  • 10 Department of Pediatrics, Beijing Key Laboratory of Molecular Diagnosis and Study on Pediatric Genetic Diseases, Peking University First Hospital, Beijing 100871, China.
  • 11 Metabolic Unit, Department of Clinical Chemistry, Amsterdam University Medical Centers, Vrije Universiteit, Amsterdam 1081 HV, the Netherlands; Amsterdam Gastroenterology & Metabolism, Amsterdam University Medical Centers, Amsterdam 1081 HV, the Netherlands.
  • 12 Department of Pediatrics, Beijing Key Laboratory of Molecular Diagnosis and Study on Pediatric Genetic Diseases, Peking University First Hospital, Beijing 100871, China; Henan Provincial Key Laboratory of Children's Genetic and Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou 450018, China.
  • 13 Department of Neonatology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht 3584 EA, the Netherlands; UMC Utrecht Brain Center, Utrecht 3584 CG, the Netherlands.
  • 14 Department of Pediatrics, Beijing Key Laboratory of Molecular Diagnosis and Study on Pediatric Genetic Diseases, Peking University First Hospital, Beijing 100871, China; Key Laboratory for Neuroscience, Ministry of Education/National Health and Family Planning Commission, Peking University, Beijing 100871, China.
  • 15 Metabolic Unit, Department of Clinical Chemistry, Amsterdam University Medical Centers, Vrije Universiteit, Amsterdam 1081 HV, the Netherlands; Amsterdam Gastroenterology & Metabolism, Amsterdam University Medical Centers, Amsterdam 1081 HV, the Netherlands; Department of Genetic Metabolic Diseases, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands; Department of Child Neurology, Emma Children's Hospital, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam and Amsterdam Neuroscience, Amsterdam 1081 HV, the Netherlands.
  • 16 Department of Child Neurology, Emma Children's Hospital, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam and Amsterdam Neuroscience, Amsterdam 1081 HV, the Netherlands; Department of Functional Genomics, Amsterdam Neuroscience, VU University, Amsterdam 1081 HV, the Netherlands.
  • 17 Molecular & Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109, USA; Departments of Computational Medicine & Bioinformatics, Psychiatry and Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
  • 18 Department of Pediatrics, Beijing Key Laboratory of Molecular Diagnosis and Study on Pediatric Genetic Diseases, Peking University First Hospital, Beijing 100871, China; Joint International Research Center of Translational and Clinical Research, Beijing 100871, China; Key Laboratory for Neuroscience, Ministry of Education/National Health and Family Planning Commission, Peking University, Beijing 100871, China.
  • 19 Department of Child Neurology, Emma Children's Hospital, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam and Amsterdam Neuroscience, Amsterdam 1081 HV, the Netherlands. Electronic address: [email protected].
PMID: 31587869 DOI: 10.1016/j.ajhg.2019.09.011
Abstract

Mechanically activated (MA) ion channels convert physical forces into electrical signals. Despite the importance of this function, the involvement of mechanosensitive ion channels in human disease is poorly understood. Here we report heterozygous missense mutations in the gene encoding the MA ion channel TMEM63A that result in an infantile disorder resembling a hypomyelinating leukodystrophy. Four unrelated individuals presented with congenital nystagmus, motor delay, and deficient myelination on serial scans in infancy, prompting the diagnosis of Pelizaeus-Merzbacher (like) disease. Genomic sequencing revealed that all four individuals carry heterozygous missense variants in the pore-forming domain of TMEM63A. These variants were confirmed to have arisen de novo in three of the four individuals. While the physiological role of TMEM63A is incompletely understood, it is highly expressed in oligodendrocytes and it has recently been shown to be a MA ion channel. Using patch clamp electrophysiology, we demonstrated that each of the modeled variants result in strongly attenuated stretch-activated currents when expressed in naive cells. Unexpectedly, the clinical evolution of all four individuals has been surprisingly favorable, with substantial improvements in neurological signs and developmental progression. In the three individuals with follow-up scans after 4 years of age, the myelin deficit had almost completely resolved. Our results suggest a previously unappreciated role for mechanosensitive ion channels in myelin development.

Keywords

MRI; TMEM63A; hypomyelination; leukodystrophy; mechanically activated (MA) ion channels; myelin.

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