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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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Heidari.pdf (Verlagsversion), 972KB
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http://www.ncbi.nlm.nih.gov/pubmed/26206890 (beliebiger Volltext)
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 Urheber:
Heidari, A., Autor
Tongsook, C., Autor
Najafipour, R., Autor
Musante, L.1, Autor           
Vasli, N., Autor
Garshasbi, M.1, Autor
Hu, H.1, Autor
Mittal, K., Autor
McNaughton, A. J., Autor
Sritharan, K., Autor
Hudson, M., Autor
Stehr, H., Autor
Talebi, S., Autor
Moradi, M., Autor
Darvish, H., Autor
Arshad Rafiq, M., Autor
Mozhdehipanah, H., Autor
Rashidinejad, A., Autor
Samiei, S., Autor
Ghadami, M., Autor
Windpassinger, C., AutorGillessen-Kaesbach, G., AutorTzschach, A.1, AutorAhmed, I., AutorMikhailov, A., AutorStavropoulos, D. J., AutorCarter, M. T., AutorKeshavarz, S., AutorAyub, M., AutorNajmabadi, H., AutorLiu, X., AutorRopers, H. H.1, Autor           Macheroux, P., AutorVincent, J. B., Autor mehr..
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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Schlagwörter: 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
 Zusammenfassung: 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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Sprache(n): eng - English
 Datum: 2015-07-232015-10-15
 Publikationsstatus: Erschienen
 Seiten: 14
 Ort, Verlag, Ausgabe: -
 Inhaltsverzeichnis: -
 Art der Begutachtung: -
 Identifikatoren: DOI: 10.1093/hmg/ddv286
ISSN: 1460-2083 (Electronic)0964-6906 (print)
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Titel: Human Molecular Genetics
Genre der Quelle: Zeitschrift
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Ort, Verlag, Ausgabe: Oxford, England : IRL Press
Seiten: - Band / Heft: 24 (20) Artikelnummer: - Start- / Endseite: 5697 - 5710 Identifikator: ISSN: 0964-6906
CoNE: https://pure.mpg.de/cone/journals/resource/954925581153