Mutation of the melastatin-related cation channel, TRPM3, underlies inherited cataract and glaucoma.

Inherited forms of cataract are a clinically important and genetically heterogeneous cause of visual impairment that usually present at an early age with or without systemic and/or other ocular abnormalities. Here we have identified a new locus for inherited cataract and high-tension glaucoma with v...

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Autores principales:	Thomas M Bennett, Donna S Mackay, Carla J Siegfried, Alan Shiels
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/71080b5b2e1c404aa67d71140bbc08b2
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spelling	oai:doaj.org-article:71080b5b2e1c404aa67d71140bbc08b22021-11-25T06:06:15ZMutation of the melastatin-related cation channel, TRPM3, underlies inherited cataract and glaucoma.1932-620310.1371/journal.pone.0104000https://doaj.org/article/71080b5b2e1c404aa67d71140bbc08b22014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/25090642/?tool=EBIhttps://doaj.org/toc/1932-6203Inherited forms of cataract are a clinically important and genetically heterogeneous cause of visual impairment that usually present at an early age with or without systemic and/or other ocular abnormalities. Here we have identified a new locus for inherited cataract and high-tension glaucoma with variable anterior segment defects, and characterized an underlying mutation in the gene coding for transient receptor potential cation channel, subfamily M, member-3 (TRPM3, melastatin-2). Genome-wide linkage analysis mapped the ocular disease locus to the pericentric region of human chromosome 9. Whole exome and custom-target next-generation sequencing detected a heterozygous A-to-G transition in exon-3 of TRPM3 that co-segregated with disease. As a consequence of alternative splicing this missense mutation was predicted to result in the substitution of isoleucine-to-methionine at codon 65 (c.195A>G; p.I65 M) of TRPM3 transcript variant 9, and at codon 8 (c.24A>G; p.I8 M) of a novel TRPM3 transcript variant expressed in human lens. In both transcript variants the I-to-M substitution was predicted in silico to exert damaging effects on protein function. Furthermore, transient expression studies of a recombinant TRPM3-GFP reporter product predicted that the I-to-M substitution introduced an alternative translation start-site located 89 codons upstream from the native initiator methionine found in eight other TRPM3 transcript variants (1-8). Collectively, these studies have provided the first evidence that TRPM3 is associated with inherited ocular disease in humans, and further provide support for the important role of this cation channel in normal eye development.Thomas M BennettDonna S MackayCarla J SiegfriedAlan ShielsPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 8, p e104000 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Thomas M Bennett Donna S Mackay Carla J Siegfried Alan Shiels Mutation of the melastatin-related cation channel, TRPM3, underlies inherited cataract and glaucoma.
description	Inherited forms of cataract are a clinically important and genetically heterogeneous cause of visual impairment that usually present at an early age with or without systemic and/or other ocular abnormalities. Here we have identified a new locus for inherited cataract and high-tension glaucoma with variable anterior segment defects, and characterized an underlying mutation in the gene coding for transient receptor potential cation channel, subfamily M, member-3 (TRPM3, melastatin-2). Genome-wide linkage analysis mapped the ocular disease locus to the pericentric region of human chromosome 9. Whole exome and custom-target next-generation sequencing detected a heterozygous A-to-G transition in exon-3 of TRPM3 that co-segregated with disease. As a consequence of alternative splicing this missense mutation was predicted to result in the substitution of isoleucine-to-methionine at codon 65 (c.195A>G; p.I65 M) of TRPM3 transcript variant 9, and at codon 8 (c.24A>G; p.I8 M) of a novel TRPM3 transcript variant expressed in human lens. In both transcript variants the I-to-M substitution was predicted in silico to exert damaging effects on protein function. Furthermore, transient expression studies of a recombinant TRPM3-GFP reporter product predicted that the I-to-M substitution introduced an alternative translation start-site located 89 codons upstream from the native initiator methionine found in eight other TRPM3 transcript variants (1-8). Collectively, these studies have provided the first evidence that TRPM3 is associated with inherited ocular disease in humans, and further provide support for the important role of this cation channel in normal eye development.
format	article
author	Thomas M Bennett Donna S Mackay Carla J Siegfried Alan Shiels
author_facet	Thomas M Bennett Donna S Mackay Carla J Siegfried Alan Shiels
author_sort	Thomas M Bennett
title	Mutation of the melastatin-related cation channel, TRPM3, underlies inherited cataract and glaucoma.
title_short	Mutation of the melastatin-related cation channel, TRPM3, underlies inherited cataract and glaucoma.
title_full	Mutation of the melastatin-related cation channel, TRPM3, underlies inherited cataract and glaucoma.
title_fullStr	Mutation of the melastatin-related cation channel, TRPM3, underlies inherited cataract and glaucoma.
title_full_unstemmed	Mutation of the melastatin-related cation channel, TRPM3, underlies inherited cataract and glaucoma.
title_sort	mutation of the melastatin-related cation channel, trpm3, underlies inherited cataract and glaucoma.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/71080b5b2e1c404aa67d71140bbc08b2
work_keys_str_mv	AT thomasmbennett mutationofthemelastatinrelatedcationchanneltrpm3underliesinheritedcataractandglaucoma AT donnasmackay mutationofthemelastatinrelatedcationchanneltrpm3underliesinheritedcataractandglaucoma AT carlajsiegfried mutationofthemelastatinrelatedcationchanneltrpm3underliesinheritedcataractandglaucoma AT alanshiels mutationofthemelastatinrelatedcationchanneltrpm3underliesinheritedcataractandglaucoma
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Mutation of the melastatin-related cation channel, TRPM3, underlies inherited cataract and glaucoma.

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