Mutations in the histamine N-methyltransferase gene, HNMT, are associated with nonsyndromic autosomal recessive intellectual disability

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 GhadamiChristian 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*

*Corresponding author for this work
19 Citations (Scopus)


Histamine (HA) acts as a neurotransmitter in the brain,which participates in the regulation ofmany biological processes including inflammation, gastric acid secretionand neuromodulation. The enzyme histamineN-methyltransferase (HNMT) inactivatesHAby transferring a methyl group from S-adenosyl-?-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 presentingwith intellectual disability.

Original languageEnglish
JournalHuman Molecular Genetics
Issue number20
Pages (from-to)5697-5710
Number of pages14
Publication statusPublished - 05.06.2015

Research Areas and Centers

  • Research Area: Medical Genetics


Dive into the research topics of 'Mutations in the histamine N-methyltransferase gene, HNMT, are associated with nonsyndromic autosomal recessive intellectual disability'. Together they form a unique fingerprint.

Cite this