Heidari A.,The Campbell Family Mental Health Research Institute |
Heidari A.,Cellular and Molecular Research Center |
Tongsook C.,University of Graz |
Najafipour R.,Cellular and Molecular Research Center |
And 36 more authors.
Human Molecular Genetics | Year: 2015
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. © The Author 2015.
PubMed | The Campbell Family Mental Health Research Institute
Type: Journal Article | Journal: Nature structural & molecular biology | Year: 2012
The 5-methylcytosine (5-mC) derivative 5-hydroxymethylcytosine (5-hmC) is abundant in the brain for unknown reasons. Here we characterize the genomic distribution of 5-hmC and 5-mC in human and mouse tissues. We assayed 5-hmC by using glucosylation coupled with restriction-enzyme digestion and microarray analysis. We detected 5-hmC enrichment in genes with synapse-related functions in both human and mouse brain. We also identified substantial tissue-specific differential distributions of these DNA modifications at the exon-intron boundary in human and mouse. This boundary change was mainly due to 5-hmC in the brain but due to 5-mC in non-neural contexts. This pattern was replicated in multiple independent data sets and with single-molecule sequencing. Moreover, in human frontal cortex, constitutive exons contained higher levels of 5-hmC relative to alternatively spliced exons. Our study suggests a new role for 5-hmC in RNA splicing and synaptic function in the brain.