title: Mutations in the histamine N-methyltransferase gene, HNMT, are associated with nonsyndromic autosomal recessive intellectual disability.
abstract: Histamine (HA) acts as a neurotransmitter in the brain, which participates in the regulation of many biological processes including inflammation, gastric acid secretion and neuromodulation. The enzyme histamine N-methyltransferase (HNMT) inactivates HA by transferring a methyl group from S-adenosyl-l-methionine to HA, and is the only well-known pathway for termination of neurotransmission actions of HA in mammalian central nervous system. We performed autozygosity mapping followed by targeted exome sequencing and identified two homozygous HNMT alterations, p.Gly60Asp and p.Leu208Pro, in patients affected with nonsyndromic autosomal recessive intellectual disability from two unrelated consanguineous families of Turkish and Kurdish ancestry, respectively. We verified the complete absence of a functional HNMT in patients using in vitro toxicology assay. Using mutant and wild-type DNA constructs as well as in silico protein modeling, we confirmed that p.Gly60Asp disrupts the enzymatic activity of the protein, and that p.Leu208Pro results in reduced protein stability, resulting in decreased HA inactivation. Our results highlight the importance of inclusion of HNMT for genetic testing of individuals presenting with intellectual disability.
authors.affiliation: Molecular Neuropsychiatry and Development (MiND) Lab, The Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada M5T 1R8, Cellular and Molecular Research Center.
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authors.affiliation: Institute of Biochemistry, Graz University of Technology, Graz 8010, Austria.
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authors.affiliation: Cellular and Molecular Research Center.
authors.forename: Reza
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authors.affiliation: Max Planck Institute of Molecular Genetics, Berlin D-14195, Germany.
authors.forename: Luciana
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authors.affiliation: Molecular Neuropsychiatry and Development (MiND) Lab, The Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada M5T 1R8.
authors.forename: Nasim
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authors.affiliation: Max Planck Institute of Molecular Genetics, Berlin D-14195, Germany, Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran 14117-13116, Iran.
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authors.affiliation: Max Planck Institute of Molecular Genetics, Berlin D-14195, Germany.
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authors.affiliation: Molecular Neuropsychiatry and Development (MiND) Lab, The Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada M5T 1R8.
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authors.affiliation: Ongwanada Genomics Lab.
authors.forename: Amy J M
authors.initials: AJ
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authors.affiliation: Molecular Neuropsychiatry and Development (MiND) Lab, The Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada M5T 1R8.
authors.forename: Kumudesh
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authors.lastname: Sritharan
authors.affiliation: Ongwanada Genomics Lab.
authors.forename: Melissa
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authors.affiliation: Department of Medicine, Stanford University, Stanford, CA 94305-5101, USA.
authors.forename: Henning
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authors.affiliation: Department of Medical Genetics, Medical University of Tehran, Tehran 14167-53955, Iran.
authors.forename: Saeid
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authors.affiliation: Cellular and Molecular Research Center.
authors.forename: Mohammad
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authors.affiliation: Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran 4739, Iran.
authors.forename: Hossein
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authors.affiliation: Molecular Neuropsychiatry and Development (MiND) Lab, The Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada M5T 1R8.
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authors.affiliation: Department of Neurology, Bou Ali Sina Hospital, Qazvin University of Medical Sciences, Qazvin 34197/59811, Iran.
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authors.affiliation: Maternal, Fetal and Neonatal Research Center, Tehran University of Medical Sciences, Tehran 1419733141, Iran.
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authors.affiliation: Department of Medical Genetics, Tehran University of Medical Sciences, Tehran 1417613151, Iran.
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authors.affiliation: Institute of Human Genetics, Medical University of Graz, Graz 8010, Austria.
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authors.forename: Gabriele
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authors.affiliation: Max Planck Institute of Molecular Genetics, Berlin D-14195, Germany.
authors.forename: Andreas
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authors.lastname: Tzschach
authors.affiliation: Molecular Neuropsychiatry and Development (MiND) Lab, The Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada M5T 1R8, Atta-ur-Rehman School of Applied Biosciences, National University of Sciences and Technology, H-12, Islamabad, Pakistan.
authors.forename: Iltaf
authors.initials: I
authors.lastname: Ahmed
authors.affiliation: Molecular Neuropsychiatry and Development (MiND) Lab, The Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada M5T 1R8.
authors.forename: Anna
authors.initials: A
authors.lastname: Mikhailov
authors.affiliation: Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: D James
authors.initials: DJ
authors.lastname: Stavropoulos
authors.affiliation: Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
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authors.initials: MT
authors.lastname: Carter
authors.affiliation: Cellular and Molecular Research Center.
authors.forename: Soraya
authors.initials: S
authors.lastname: Keshavarz
authors.affiliation: Division of Developmental Disabilities, Department of Psychiatry, Queen's University, Kingston, ON, Canada K7L7X3.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ayub
authors.affiliation: Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran 19857, Iran, Kariminejad-Najmabadi Pathology and Genetics Center, Tehran 14667, Iran.
authors.forename: Hossein
authors.initials: H
authors.lastname: Najmabadi
authors.affiliation: Ongwanada Genomics Lab.
authors.forename: Xudong
authors.initials: X
authors.lastname: Liu
authors.affiliation: Max Planck Institute of Molecular Genetics, Berlin D-14195, Germany.
authors.forename: Hans Hilger
authors.initials: HH
authors.lastname: Ropers
authors.affiliation: Institute of Biochemistry, Graz University of Technology, Graz 8010, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Macheroux
authors.affiliation: Molecular Neuropsychiatry and Development (MiND) Lab, The Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada M5T 1R8, Department of Psychiatry, University of Toronto, Toronto, ON, Canada M5T 1R8 and Institute of Medical Science, University of Toronto, Toronto, ON, Canada M5S 1A8 john.vincent@camh.ca.
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authors.initials: JB
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mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D020134:Catalytic Domain; D002648:Child; D002675:Child, Preschool; D003198:Computer Simulation; D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D005808:Genes, Recessive; D006637:Histamine N-Methyltransferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000201:enzymology / Q000235:genetics*; D007493:Iraq; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D016415:Sequence Alignment; D014421:Turkey; D044465:White People / Q000235:genetics
chemical_list: D006637:Histamine N-Methyltransferase