1. Academic Validation
  2. Disruption of the methyltransferase-like 23 gene METTL23 causes mild autosomal recessive intellectual disability

Disruption of the methyltransferase-like 23 gene METTL23 causes mild autosomal recessive intellectual disability

  • Hum Mol Genet. 2014 Aug 1;23(15):4015-23. doi: 10.1093/hmg/ddu115.
Marie Bernkopf 1 Gerald Webersinke 1 Chanakan Tongsook 2 Chintan N Koyani 3 Muhammad A Rafiq 4 Muhammad Ayaz 5 Doris Müller 6 Christian Enzinger 7 Muhammad Aslam 5 Farooq Naeem 8 Kurt Schmidt 9 Karl Gruber 10 Michael R Speicher 11 Ernst Malle 3 Peter Macheroux 2 Muhammad Ayub 8 John B Vincent 12 Christian Windpassinger 13 Hans-Christoph Duba 6
Affiliations

Affiliations

  • 1 Laboratory of Molecular Biology and Tumorcytogenetics, Department of Internal Medicine, Krankenhaus der Barmherzigen Schwestern, Linz, Austria.
  • 2 Institute of Biochemistry, Graz University of Technology, Graz, Austria.
  • 3 Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
  • 4 Molecular Neuropsychiatry and Development (MiND) Lab, The Campbell Family Brain Research Institute, The Centre for Addiction & Mental Health (CAMH), Toronto, ON, Canada.
  • 5 Lahore Institute of Research and Development, Lahore, Punjab Province, Pakistan.
  • 6 Department of Human Genetics, Landes-Frauen und Kinderklinik, Linz, Austria.
  • 7 Department of Neurology and.
  • 8 Lahore Institute of Research and Development, Lahore, Punjab Province, Pakistan Division of Developmental Disabilities, Department of Psychiatry, Queen's University, Kingston, ON, Canada.
  • 9 Department of Pharmacology and Toxicology, Karl-Franzens University Graz, Graz, Austria.
  • 10 Institute of Molecular Biosciences, University of Graz, Graz, Austria.
  • 11 Institute of Human Genetics, Medical University of Graz, Graz, Austria.
  • 12 Molecular Neuropsychiatry and Development (MiND) Lab, The Campbell Family Brain Research Institute, The Centre for Addiction & Mental Health (CAMH), Toronto, ON, Canada Department of Psychiatry and Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
  • 13 Institute of Human Genetics, Medical University of Graz, Graz, Austria christian.windpassinger@medunigraz.at.
Abstract

We describe the characterization of a gene for mild nonsyndromic autosomal recessive intellectual disability (ID) in two unrelated families, one from Austria, the other from Pakistan. Genome-wide single nucleotide polymorphism microarray analysis enabled us to define a region of homozygosity by descent on chromosome 17q25. Whole-exome Sequencing and analysis of this region in an affected individual from the Austrian family identified a 5 bp frameshifting deletion in the METTL23 gene. By means of Sanger Sequencing of METTL23, a nonsense mutation was detected in a consanguineous ID family from Pakistan for which homozygosity-by-descent mapping had identified a region on 17q25. Both changes lead to truncation of the putative METTL23 protein, which disrupts the predicted catalytic domain and alters the cellular localization. 3D-modelling of the protein indicates that METTL23 is strongly predicted to function as an S-adenosyl-methionine (SAM)-dependent methyltransferase. Expression analysis of METTL23 indicated a strong association with heat shock proteins, which suggests that these may act as a putative substrate for methylation by METTL23. A number of methyltransferases have been described recently in association with ID. Disruption of METTL23 presented here supports the importance of methylation processes for intact neuronal function and brain development.

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