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

Heidari, A., Tongsook, C., Najafipour, R., Musante, L., Vasli, N., Garshasbi, M., et al. (2015). Mutations in the histamine N-methyltransferase gene, HNMT, are associated with nonsyndromic autosomal recessive intellectual disability. Human Molecular Genetics, 24(20), 5697-5710. doi:10.1093/hmg/ddv286.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0000-C6B3-6 Version Permalink: http://hdl.handle.net/21.11116/0000-0000-C6B4-5
Genre: Journal Article

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 Creators:
Heidari, A., Author
Tongsook, C., Author
Najafipour, R., Author
Musante, L.1, Author              
Vasli, N., Author
Garshasbi, M.1, Author
Hu, H.1, Author
Mittal, K., Author
McNaughton, A. J., Author
Sritharan, K., Author
Hudson, M., Author
Stehr, H., Author
Talebi, S., Author
Moradi, M., Author
Darvish, H., Author
Arshad Rafiq, M., Author
Mozhdehipanah, H., Author
Rashidinejad, A., Author
Samiei, S., Author
Ghadami, M., Author
Windpassinger, C., AuthorGillessen-Kaesbach, G., AuthorTzschach, A.1, AuthorAhmed, I., AuthorMikhailov, A., AuthorStavropoulos, D. J., AuthorCarter, M. T., AuthorKeshavarz, S., AuthorAyub, M., AuthorNajmabadi, H., AuthorLiu, X., AuthorRopers, H. H.1, Author              Macheroux, P., AuthorVincent, J. B., Author more..
Affiliations:
1Emeritus Group of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2385695              

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Free keywords: Adolescent Adult Amino Acid Sequence Catalytic Domain Child Child, Preschool Computer Simulation DNA Mutational Analysis European Continental Ancestry Group/genetics 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
 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.

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Language(s): eng - English
 Dates: 2015-07-232015-10-15
 Publication Status: Published in print
 Pages: 14
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: DOI: 10.1093/hmg/ddv286
ISSN: 1460-2083 (Electronic)0964-6906 (print)
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Title: Human Molecular Genetics
Source Genre: Journal
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Publ. Info: Oxford, England : IRL Press
Pages: - Volume / Issue: 24 (20) Sequence Number: - Start / End Page: 5697 - 5710 Identifier: ISSN: 0964-6906
CoNE: https://pure.mpg.de/cone/journals/resource/954925581153