Mutations in the histamine<i>N</i>-methyltransferase gene,<i>HNMT</i>, are associated with nonsyndromic autosomal recessive intellectual disability

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; Moradi, Mohammad; Darvish, Hossein; Rafiq, Muhammad; Mozhdehipanah, Hossein; Rashidinejad, Ali; Samiei, Shahram; Ghadami, Mohsen; Windpassinger, Christian; Gillessen‐Kaesbach, Gabriele; Tzschach, Andreas; Ahmed, Iltaf; Mikhailov, Anna; Stavropoulos, Dimitrios J.; Carter, Melissa T.; Keshavarz, S; Ayub, Muhammad; Najmabadi, Hossein; Li, Xudong; Ropers, Hans Hilger; Macheroux, Peter; Vincent, John B.

doi:10.1093/hmg/ddv286

Cited by 28 publications

(21 citation statements)

References 40 publications

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“…However, large scale ID family studies are making significant inroads 11 . Homozygosity mapping has been proven to be an effective method for gene identification in consanguineous populations [11][12][13][14][15][16][17] . Consanguineous marriages lead to a marked increase in frequency of severe recessive disorders 18 .…”

Section: Introductionmentioning

confidence: 99%

Mapping Autosomal Recessive Intellectual Disability: Combined Microarray and Exome Sequencing Identifies 26 Novel Candidate Genes in 192 Consanguineous Families

Harripaul

Vasli

Mikhailov

et al. 2016

Preprint

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4Approximately 1% of the global population is affected by intellectual disability (ID), and the majority receive no molecular diagnosis. Previous studies have indicated high levels of genetic heterogeneity, with estimates of more than 2500 autosomal ID genes, the majority of which are autosomal recessive (AR). Here, we combined microarray genotyping, homozygosity-by-descent (HBD) mapping, copy number variation (CNV) analysis, and whole exome sequencing (WES) to identify disease genes/mutations in 192 multiplex Pakistani and Iranian consanguineous families with non-syndromic ID. We identified definite or candidate mutations (or CNVs) in 51% of families in 72 different genes, including 26 not previously reported for ARID. The new ARID genes include nine with loss-of-function mutations (ABI2, MAPK8, MPDZ, PIDD1, SLAIN1, TBC1D23, TRAPPC6B, UBA7, and USP44), and missense mutations include the first reports of variants in BDNF or TET1 associated with ID. The genes identified also showed overlap with de novo gene sets for other neuropsychiatric disorders. Transcriptional studies showed prominent expression in the prenatal brain. The high yield of AR mutations for ID indicated that this approach has excellent clinical potential and should inform clinical diagnostics, including clinical whole exome and genome sequencing, for populations in which consanguinity is common. As with other AR disorders, the relevance will also apply to outbred populations.

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Section: Introductionmentioning

confidence: 99%

Mapping Autosomal Recessive Intellectual Disability: Combined Microarray and Exome Sequencing Identifies 26 Novel Candidate Genes in 192 Consanguineous Families

Harripaul

Vasli

Mikhailov

et al. 2016

Preprint

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“…McCarthy et al (2014) also reported de novo mutations in schizophrenia patients in other ID genes such as TRAPPC9 and HUWE1. Additionally, Heidari et al (2015) reporting the use of WES to identify missense mutations in the histamine N-methyltransferase gene HNMTas a cause of nonsyndromic autosomal recessive ID, also made the point that rare heterozygous loss CNVs or LoF mutations disrupting HNMT have also been reported for bipolar disorder (Zhang et al 2009), autism spectrum disorder (DECI-PHER), and for schizophrenia (Genebook). The issue of pleiotropy across ID and neuropsychiatric disorders was raised in a recent publication by Li et al (2015).…”

Section: Discussionmentioning

confidence: 99%

The Use of Next-Generation Sequencing for Research and Diagnostics for Intellectual Disability

Harripaul

Noor

Ayub

et al. 2017

Cold Spring Harb Perspect Med

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“…An A939G polymorphism is related to several brain disorders such as myasthenia gravis and ADHD [59,68]. Recently, Heidari et al reported that two novel mutations in the human HNMT gene (G179A and T632C) impairs its enzymatic activity, leading to intellectual disability [69,70].…”

Section: Hnmt and Human Brain Diseasesmentioning

confidence: 99%

Histamine N-Methyltransferase in the Brain

Yoshikawa

Nakamura

Yanai

2019

IJMS

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Brain histamine is a neurotransmitter and regulates diverse physiological functions. Previous studies have shown the involvement of histamine depletion in several neurological disorders, indicating the importance of drug development targeting the brain histamine system. Histamine N-methyltransferase (HNMT) is a histamine-metabolising enzyme expressed in the brain. Although pharmacological studies using HNMT inhibitors have been conducted to reveal the direct involvement of HNMT in brain functions, HNMT inhibitors with high specificity and sufficient blood–brain barrier permeability have not been available until now. Recently, we have phenotyped Hnmt-deficient mice to elucidate the importance of HNMT in the central nervous system. Hnmt disruption resulted in a robust increase in brain histamine concentration, demonstrating the essential role of HNMT in the brain histamine system. Clinical studies have suggested that single nucleotide polymorphisms of the human HNMT gene are associated with several brain disorders such as Parkinson’s disease and attention deficit hyperactivity disorder. Postmortem studies also have indicated that HNMT expression is altered in human brain diseases. These findings emphasise that an increase in brain histamine levels by novel HNMT inhibitors could contribute to the improvement of brain disorders.

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Mutations in the histamineN-methyltransferase gene,HNMT, are associated with nonsyndromic autosomal recessive intellectual disability

Cited by 28 publications

References 40 publications

Mapping Autosomal Recessive Intellectual Disability: Combined Microarray and Exome Sequencing Identifies 26 Novel Candidate Genes in 192 Consanguineous Families

Mapping Autosomal Recessive Intellectual Disability: Combined Microarray and Exome Sequencing Identifies 26 Novel Candidate Genes in 192 Consanguineous Families

The Use of Next-Generation Sequencing for Research and Diagnostics for Intellectual Disability

Histamine N-Methyltransferase in the Brain

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