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

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 [email protected].

PMID: 24626631 DOI: 10.1093/hmg/ddu115

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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