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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.

journal_name

Hum Mol Genet

journal_title

Human molecular genetics

authors

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,

doi

10.1093/hmg/ddv286

subject

Has Abstract

pub_date

2015-10-15 00:00:00

pages

5697-710

issue

20

eissn

0964-6906

issn

1460-2083

pii

ddv286

journal_volume

24

pub_type

杂志文章

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