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SHR Neuro Cancer Cardio Lipid

Heidari, A; Tongsook, C; Najafipour, R; Musante, L; Vasli, N; Garshasbi, M; Hu, H; Mittal, K; McNaughton, AJ; Sritharan, K; Hudson, M; Stehr, H; Talebi, S; Moradi, M; Darvish, H; Arshad Rafiq, M; Mozhdehipanah, H; Rashidinejad, A; Samiei, S; Ghadami, M; Windpassinger, C; Gillessen-Kaesbach, G; Tzschach, A; Ahmed, I; Mikhailov, A; Stavropoulos, DJ; Carter, MT; Keshavarz, S; Ayub, M; Najmabadi, H; Liu, X; Ropers, HH; Macheroux, P; Vincent, JB.
Mutations in the histamine N-methyltransferase gene, HNMT, are associated with nonsyndromic autosomal recessive intellectual disability.
Hum Mol Genet. 2015; 24(20):5697-5710 (- Case Report) [OPEN ACCESS]
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Authors Med Uni Graz:
Windpassinger Christian

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Number of Figures: 7
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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. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email:
Find related publications in this database (using NLM MeSH Indexing)
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
Histamine N-Methyltransferase - metabolism
Humans -
Infant -
Intellectual Disability - enzymology
Intellectual Disability - genetics
Intellectual Disability -
Male -
Molecular Sequence Data -
Mutation, Missense -
Pedigree -
Sequence Alignment -
Sequence Alignment -

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