Mutations in the Histamine N-Methyltransferase Gene, Hnmt, Are Associated With Nonsyndromic Autosomal Recessive Intellectual Disability

Mutations in the Histamine N-Methyltransferase Gene, Hnmt, Are Associated With Nonsyndromic Autosomal Recessive Intellectual Disability Publisher Pubmed

Heidari A^{1, 2} ; Tongsook C⁴ ; Najafipour R² ; Musante L⁵ ; Vasli N¹ ; Garshasbi M^{5, 6} ; Hu H⁵ ; Mittal K¹ ; Mcnaughton AJM⁷ ; Sritharan K¹ ; Hudson M⁷ ; Stehr H⁹ ; Talebi S¹⁰ ; Moradi M² Show All Authors

Heidari A^{1, 2}
Tongsook C⁴
Najafipour R²
Musante L⁵
Vasli N¹
Garshasbi M^{5, 6}
Hu H⁵
Mittal K¹
Mcnaughton AJM⁷
Sritharan K¹
Hudson M⁷
Stehr H⁹
Talebi S¹⁰
Moradi M²
Darvish H¹¹
Rafiq MA¹
Mozhdehipanah H³
Rashidinejad A¹²
Samiei S¹³
Ghadami M¹⁴
Windpassinger C¹⁵
Gillessenkaesbach G¹⁶
Tzschach A^{5, 24}
Ahmed I^{1, 17}
Mikhailov A¹
James Stavropoulos D¹⁸
Carter MT¹⁹
Keshavarz S²
Ayub M⁸
Najmabadi H^{20, 21}
Liu X⁷
Ropers HH⁵
Macheroux P⁴
Vincent JB^{1, 22, 23}

Show Affiliations

1. Molecular Neuropsychiatry and Development (MiND) Lab, The Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, M5T 1R8, ON, Canada
2. Cellular and Molecular Research Center, India
3. Department of Neurology, Bou Ali Sina Hospital, Qazvin University of Medical Sciences, Qazvin, 34197/59811, Iran
4. Institute of Biochemistry, Graz University of Technology, Graz, 8010, Austria
5. Max Planck Institute of Molecular Genetics, Berlin, D-14195, Germany
6. Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, 14117-13116, Iran
7. Ongwanada Genomics Lab, Kingston, K7L7X3, ON, Canada
8. Division of Developmental Disabilities, Department of Psychiatry, Queen's University, Kingston, K7L7X3, ON, Canada
9. Department of Medicine, Stanford University, Stanford, 94305-5101, CA, United States
10. Department of Medical Genetics, Medical University of Tehran, Tehran, 14167-53955, Iran
11. Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, 4739, Iran
12. Fetal and Neonatal Research Center, Tehran University of Medical Sciences, Tehran, 1419733141, Iran
13. Blood Transfusion Research Center, Tehran, 1449613111, Iran
14. Department of Medical Genetics, Tehran University of Medical Sciences, Tehran, 1417613151, Iran
15. Institute of Human Genetics, Medical University of Graz, Graz, 8010, Austria
16. Institut fur Humangenetik, Universitat zu Lubeck, Lubeck, 23562, Germany
17. Atta-ur-Rehman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, H-12, Pakistan
18. Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada
19. Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
20. Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, 19857, Iran
21. Kariminejad-Najmabadi Pathology and Genetics Center, Tehran, 14667, Iran
22. Department of Psychiatry, University of Toronto, Toronto, M5T 1R8, ON, Canada
23. Institute of Medical Science, University of Toronto, Toronto, M5S 1A8, ON, Canada
24. Institute of Clinical Genetics, Technische Universitat Dresden, Dresden, 01307, Germany

Source: Human Molecular Genetics Published:2015

Abstract

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.

2. Mutation in Twinkle in a Large Iranian Family With Progressive External Ophthalmoplegia, Myopathy, Dysphagia and Dysphonia, and Behavior Change, Archives of Iranian Medicine (2016)

3. Distinct Genetic Variation and Heterogeneity of the Iranian Population, PLoS Genetics (2019)

4. Frequencies of Six (Five Novel) Str Markers Linked to Tusc3 (Mrt7) or Nsun2 (Mrt5) Genes Used for Homozygosity Mapping of Recessive Intellectual Disability, Clinical Laboratory (2015)

5. Effect of Inbreeding on Intellectual Disability Revisited by Trio Sequencing, Clinical Genetics (2019)

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Reza Malekzadeh (1)

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Style	Citing Format
MLA	Heidari A, et al.. "Mutations in the Histamine N-Methyltransferase Gene, Hnmt, Are Associated With Nonsyndromic Autosomal Recessive Intellectual Disability." Human Molecular Genetics, vol. 24, no. 20, 2015, pp. 5697-5710.
APA	Heidari A, Tongsook C, Najafipour R, Musante L, Vasli N, Garshasbi M, Hu H, Mittal K, Mcnaughton AJM, Sritharan K, Hudson M, Stehr H, Talebi S, Moradi M, Darvish H, Rafiq MA, Mozhdehipanah H, Rashidinejad A, Samiei S, ... Vincent JB (2015). Mutations in the Histamine N-Methyltransferase Gene, Hnmt, Are Associated With Nonsyndromic Autosomal Recessive Intellectual Disability. Human Molecular Genetics, 24(20), 5697-5710.
Chicago	Heidari A, Tongsook C, Najafipour R, Musante L, Vasli N, Garshasbi M, Hu H, et al.. "Mutations in the Histamine N-Methyltransferase Gene, Hnmt, Are Associated With Nonsyndromic Autosomal Recessive Intellectual Disability." Human Molecular Genetics 24, no. 20 (2015): 5697-5710.
Harvard	Heidari A et al. (2015) 'Mutations in the Histamine N-Methyltransferase Gene, Hnmt, Are Associated With Nonsyndromic Autosomal Recessive Intellectual Disability', Human Molecular Genetics, 24(20), pp. 5697-5710.
Vancouver	Heidari A, Tongsook C, Najafipour R, Musante L, Vasli N, Garshasbi M, et al.. Mutations in the Histamine N-Methyltransferase Gene, Hnmt, Are Associated With Nonsyndromic Autosomal Recessive Intellectual Disability. Human Molecular Genetics. 2015;24(20):5697-5710.
BibTex	@article{ author = {Heidari A and Tongsook C and Najafipour R and Musante L and Vasli N and Garshasbi M and Hu H and Mittal K and Mcnaughton AJM and Sritharan K and Hudson M and Stehr H and Talebi S and Moradi M and Darvish H and Rafiq MA and Mozhdehipanah H and Rashidinejad A and Samiei S and Ghadami M and Windpassinger C and Gillessenkaesbach G and Tzschach A and Ahmed I and Mikhailov A and James Stavropoulos D and Carter MT and Keshavarz S and Ayub M and Najmabadi H and Liu X and Ropers HH and Macheroux P and Vincent JB}, title = {Mutations in the Histamine N-Methyltransferase Gene, Hnmt, Are Associated With Nonsyndromic Autosomal Recessive Intellectual Disability}, journal = {Human Molecular Genetics}, volume = {24}, number = {20}, pages = {5697-5710}, year = {2015} }
RIS	TY - JOUR AU - Heidari A AU - Tongsook C AU - Najafipour R AU - Musante L AU - Vasli N AU - Garshasbi M AU - Hu H AU - Mittal K AU - Mcnaughton AJM AU - Sritharan K AU - Hudson M AU - Stehr H AU - Talebi S AU - Moradi M AU - Darvish H AU - Rafiq MA AU - Mozhdehipanah H AU - Rashidinejad A AU - Samiei S AU - Ghadami M AU - Windpassinger C AU - Gillessenkaesbach G AU - Tzschach A AU - Ahmed I AU - Mikhailov A AU - James Stavropoulos D AU - Carter MT AU - Keshavarz S AU - Ayub M AU - Najmabadi H AU - Liu X AU - Ropers HH AU - Macheroux P AU - Vincent JB TI - Mutations in the Histamine N-Methyltransferase Gene, Hnmt, Are Associated With Nonsyndromic Autosomal Recessive Intellectual Disability JO - Human Molecular Genetics VL - 24 IS - 20 SP - 5697 EP - 5710 PY - 2015 ER -

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