title: Disruption of the methyltransferase-like 23 gene METTL23 causes mild autosomal recessive intellectual disability.
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.
authors.affiliation: Laboratory of Molecular Biology and Tumorcytogenetics, Department of Internal Medicine, Krankenhaus der Barmherzigen Schwestern, Linz, Austria.
authors.forename: Marie
authors.initials: M
authors.lastname: Bernkopf
authors.affiliation: Laboratory of Molecular Biology and Tumorcytogenetics, Department of Internal Medicine, Krankenhaus der Barmherzigen Schwestern, Linz, Austria.
authors.forename: Gerald
authors.initials: G
authors.lastname: Webersinke
authors.affiliation: Institute of Biochemistry, Graz University of Technology, Graz, Austria.
authors.forename: Chanakan
authors.initials: C
authors.lastname: Tongsook
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
authors.forename: Chintan N
authors.initials: CN
authors.lastname: Koyani
authors.affiliation: Molecular Neuropsychiatry and Development (MiND) Lab, The Campbell Family Brain Research Institute, The Centre for Addiction & Mental Health (CAMH), Toronto, ON, Canada.
authors.forename: Muhammad A
authors.initials: MA
authors.lastname: Rafiq
authors.affiliation: Lahore Institute of Research and Development, Lahore, Punjab Province, Pakistan.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ayaz
authors.affiliation: Department of Human Genetics, Landes-Frauen und Kinderklinik, Linz, Austria.
authors.forename: Doris
authors.initials: D
authors.lastname: Müller
authors.affiliation: Department of Neurology and.
authors.forename: Christian
authors.initials: C
authors.lastname: Enzinger
authors.affiliation: Lahore Institute of Research and Development, Lahore, Punjab Province, Pakistan.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Aslam
authors.affiliation: Lahore Institute of Research and Development, Lahore, Punjab Province, Pakistan Division of Developmental Disabilities, Department of Psychiatry, Queen's University, Kingston, ON, Canada.
authors.forename: Farooq
authors.initials: F
authors.lastname: Naeem
authors.affiliation: Department of Pharmacology and Toxicology, Karl-Franzens University Graz, Graz, Austria.
authors.forename: Kurt
authors.initials: K
authors.lastname: Schmidt
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Graz, Austria.
authors.forename: Karl
authors.initials: K
authors.lastname: Gruber
authors.affiliation: Institute of Human Genetics, Medical University of Graz, Graz, Austria.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Speicher
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
authors.forename: Ernst
authors.initials: E
authors.lastname: Malle
authors.affiliation: Institute of Biochemistry, Graz University of Technology, Graz, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Macheroux
authors.affiliation: Lahore Institute of Research and Development, Lahore, Punjab Province, Pakistan Division of Developmental Disabilities, Department of Psychiatry, Queen's University, Kingston, ON, Canada.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ayub
authors.affiliation: 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.
authors.forename: John B
authors.initials: JB
authors.lastname: Vincent
authors.affiliation: Institute of Human Genetics, Medical University of Graz, Graz, Austria christian.windpassinger@medunigraz.at.
authors.forename: Christian
authors.initials: C
authors.lastname: Windpassinger
authors.affiliation: Department of Human Genetics, Landes-Frauen und Kinderklinik, Linz, Austria.
authors.forename: Hans-Christoph
authors.initials: HC
authors.lastname: Duba
mesh_terms: D001483:Base Sequence; D002648:Child; D002886:Chromosomes, Human, Pair 17; D003241:Consanguinity; D059472:Exome; D005260:Female; D005808:Genes, Recessive; D006720:Homozygote; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008780:Methyltransferases / Q000235:genetics*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree
chemical_list: D008780:Methyltransferases; C468275:METTL3 protein, human