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: Abolfazl Heidari, Chanakan Tongsook, Reza Najafipour, Luciana Musante, Nasim Vasli, Masoud Garshasbi, Hao Hu, Kirti Mittal, Amy J M McNaughton, Kumudesh Sritharan, Melissa Hudson, Henning Stehr, Saeid Talebi, Mohammad Moradi, Hossein Darvish, Muhammad Arshad Rafiq, Hossein Mozhdehipanah, Ali Rashidinejad, Shahram Samiei, Mohsen Ghadami, Christian Windpassinger, Gabriele Gillessen-Kaesbach, Andreas Tzschach, Iltaf Ahmed, Anna Mikhailov, D James Stavropoulos, Melissa T Carter, Soraya Keshavarz, Muhammad Ayub, Hossein Najmabadi, Xudong Liu, Hans Hilger Ropers, Peter Macheroux, John B Vincent
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 24 Issue 20 Pg. 5697-710 (Oct 15 2015) ISSN: 1460-2083 [Electronic] England
• PMID: 26206890 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• Histamine N-Methyltransferase

Topics

• Adolescent
• Adult
• Amino Acid Sequence
• Catalytic Domain
• Child
• Child, Preschool
• Computer Simulation
• DNA Mutational Analysis
• Exome
• Female
• Genes, Recessive
• Histamine N-Methyltransferase (genetics, metabolism)
• Humans
• Infant
• Intellectual Disability (enzymology, genetics)
• Iraq
• Male
• Molecular Sequence Data
• Mutation, Missense
• Pedigree
• Sequence Alignment
• Turkey
• White People (genetics)