Heidari Abolfazl, Tongsook Chanakan, Najafipour Reza, Musante Luciana, Vasli Nasim, Garshasbi Masoud, Hu Hao, Mittal Kirti, McNaughton Amy J M, Sritharan Kumudesh, Hudson Melissa, Stehr Henning, Talebi Saeid, Moradi Mohammad, Darvish Hossein, Arshad Rafiq Muhammad, Mozhdehipanah Hossein, Rashidinejad Ali, Samiei Shahram, Ghadami Mohsen, Windpassinger Christian, Gillessen-Kaesbach Gabriele, Tzschach Andreas, Ahmed Iltaf, Mikhailov Anna, Stavropoulos D James, Carter Melissa T, Keshavarz Soraya, Ayub Muhammad, Najmabadi Hossein, Liu Xudong, Ropers Hans Hilger, Macheroux Peter, Vincent John B
Molecular Neuropsychiatry and Development (MiND) Lab, The Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada M5T 1R8, Cellular and Molecular Research Center.
Institute of Biochemistry, Graz University of Technology, Graz 8010, Austria.
Hum Mol Genet. 2015 Oct 15;24(20):5697-710. doi: 10.1093/hmg/ddv286. Epub 2015 Jul 23.
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.
组胺(HA)在大脑中作为一种神经递质,参与包括炎症、胃酸分泌和神经调节在内的许多生物过程的调节。组胺N - 甲基转移酶(HNMT)通过将S - 腺苷 - L - 甲硫氨酸的甲基转移到HA上来使HA失活,并且是哺乳动物中枢神经系统中HA神经传递作用终止的唯一已知途径。我们进行了纯合性定位,随后进行靶向外显子组测序,并分别在来自两个具有土耳其和库尔德血统的不相关近亲家庭的非综合征常染色体隐性智力残疾患者中鉴定出两种纯合的HNMT改变,即p.Gly60Asp和p.Leu208Pro。我们使用体外毒理学试验证实患者体内完全不存在功能性HNMT。通过使用突变型和野生型DNA构建体以及计算机蛋白质建模,我们证实p.Gly60Asp破坏了该蛋白质的酶活性,并且p.Leu208Pro导致蛋白质稳定性降低,从而导致HA失活减少。我们的结果突出了将HNMT纳入智力残疾个体基因检测的重要性。