De novo substitutions of TRPM3 cause intellectual disability and epilepsy.
Journal
European journal of human genetics : EJHG
ISSN: 1476-5438
Titre abrégé: Eur J Hum Genet
Pays: England
ID NLM: 9302235
Informations de publication
Date de publication:
10 2019
10 2019
Historique:
received:
18
01
2019
accepted:
25
06
2019
revised:
26
04
2019
pubmed:
7
7
2019
medline:
17
6
2020
entrez:
7
7
2019
Statut:
ppublish
Résumé
The developmental and epileptic encephalopathies (DEE) are a heterogeneous group of chronic encephalopathies frequently associated with rare de novo nonsynonymous coding variants in neuronally expressed genes. Here, we describe eight probands with a DEE phenotype comprising intellectual disability, epilepsy, and hypotonia. Exome trio analysis showed de novo variants in TRPM3, encoding a brain-expressed transient receptor potential channel, in each. Seven probands were identically heterozygous for a recurrent substitution, p.(Val837Met), in TRPM3's S4-S5 linker region, a conserved domain proposed to undergo conformational change during gated channel opening. The eighth individual was heterozygous for a proline substitution, p.(Pro937Gln), at the boundary between TRPM3's flexible pore-forming loop and an adjacent alpha-helix. General-population truncating variants and microdeletions occur throughout TRPM3, suggesting a pathomechanism other than simple haploinsufficiency. We conclude that de novo variants in TRPM3 are a cause of intellectual disability and epilepsy.
Identifiants
pubmed: 31278393
doi: 10.1038/s41431-019-0462-x
pii: 10.1038/s41431-019-0462-x
pmc: PMC6777445
doi:
Substances chimiques
TRPM Cation Channels
0
TRPM3 protein, human
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1611-1618Références
Bowling KM, Thompson ML, Amaral MD, Finnila CR, Hiatt SM, Engel KL, et al. Genomic diagnosis for children with intellectual disability and/or developmental delay. Genome Med. 2017;9:43.
doi: 10.1186/s13073-017-0433-1
Hamdan FF, Myers CT, Cossette P, Lemay P, Spiegelman D, Laporte AD, et al. High rate of recurrent de novo mutations in developmental and epileptic encephalopathies. Am J Hum Genet. 2017;101:664–85.
doi: 10.1016/j.ajhg.2017.09.008
Martínez F, Caro-Llopis A, Roselló M, Oltra S, Mayo S, Monfort S, et al. High diagnostic yield of syndromic intellectual disability by targeted next-generation sequencing. J Med Genet. 2016;54:87–92.
doi: 10.1136/jmedgenet-2016-103964
Clapham DE. TRP channels as cellular sensors. Nature. 2003;426:517–24.
doi: 10.1038/nature02196
Nilius B. TRP channels in disease. Biochim Biophys Acta. 2007;1772:805–12.
doi: 10.1016/j.bbadis.2007.02.002
Sobreira N, Schiettecatte F, Valle D, Hamosh A. GeneMatcher: a matching tool for connecting investigators with an interest in the same gene. Hum Mutat. 2015;36:928–30.
doi: 10.1002/humu.22844
Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536:285–91.
doi: 10.1038/nature19057
Kumar P, Henikoff S, Ng PC. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc. 2009;4:1073–81.
doi: 10.1038/nprot.2009.86
Ramensky V. Human non-synonymous SNPs: server and survey. Nucleic Acids Res. 2002;30:3894–900.
doi: 10.1093/nar/gkf493
Kircher M, Witten DM, Jain P, Oroak BJ, Cooper GM, Shendure J. A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet. 2014;46:310–5.
doi: 10.1038/ng.2892
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17:405–24.
doi: 10.1038/gim.2015.30
Macdonald JR, Ziman R, Yuen RKC, Feuk L, Scherer SW. The database of genomic variants: a curated collection of structural variation in the human genome. Nucleic Acids Res. 2013;42:D986–992.
doi: 10.1093/nar/gkt958
Duan J, Li Z, Li J, Hulse RE, Santa-Cruz A, Valinsky WC, et al. Structure of the mammalian TRPM7, a magnesium channel required during embryonic development. Proc Natl Acad Sci USA. 2018;115:e8201–10.
doi: 10.1073/pnas.1810719115
Horn R. Coupled movements in voltage-gated ion channels. J Gen Physiol. 2002;120:449–53.
doi: 10.1085/jgp.20028658
Xie J, Sun B, Du J, Yang W, Chen HC, Overton JD, et al. Phosphatidylinositol 4,5-bisphosphate (PIP2) controls magnesium gatekeeper TRPM6 activity. Sci Rep. 2011;1:146.
doi: 10.1038/srep00146
Held K, Voets T, Vriens J. TRPM3 in temperature sensing and beyond. Temperature. 2015;2:201–13.
doi: 10.4161/23328940.2014.988524
Held K, Gruss F, Aloi VD, Janssens A, Ulens C, Voets T, et al. Mutations in the voltage-sensing domain affect the alternative ion permeation pathway in the TRPM3 channel. J Physiol. 2018;596:2413–32.
doi: 10.1113/JP274124
Tóth BI, Konrad M, Ghosh D, Mohr F, Halaszovich CR, Leitner MG, et al. Regulation of the transient receptor potential channel TRPM3 by phosphoinositides. J Gen Physiol. 2015;146:51–63.
doi: 10.1085/jgp.201411339
Bennett TM, Mackay DS, Siegfried CJ, Shiels A. Mutation of the melastatin-related cation channel, TRPM3, underlies inherited cataract and glaucoma. PLoS ONE. 2014;9:e104000.
doi: 10.1371/journal.pone.0104000
Pagnamenta AT, Holt R, Yusuf M, Pinto D, Wing K, Betancur C, et al. A family with autism and rare copy number variants disrupting the Duchenne/Becker muscular dystrophy gene DMD and TRPM3. J Neurodev Dis. 2011;3:124–31.
doi: 10.1007/s11689-011-9076-5
Kuniba H, Yoshiura K-I, Kondoh T, Ohashi H, Kurosawa K, Tonoki H, et al. Molecular karyotyping in 17 patients and mutation screening in 41 patients with Kabuki syndrome. J Hum Genet. 2009;54:304–9.
doi: 10.1038/jhg.2009.30
Grimm C, Kraft R, Sauerbruch S, Schultz G, Harteneck C. Molecular and functional characterization of the melastatin-related cation channel TRPM3. J Biol Chem. 2003;278:21493–501.
doi: 10.1074/jbc.M300945200
Hoffmann A, Grimm C, Kraft R, Goldbaum O, Wrede A, Nolte C, et al. TRPM3 is expressed in sphingosine-responsive myelinating oligodendrocytes. J Neurochem. 2010;114:654–65.
doi: 10.1111/j.1471-4159.2010.06644.x
Vandewauw I, Clercq KD, Mulier M, Held K, Pinto S, Van Ranst N, et al. A TRP channel trio mediates acute noxious heat sensing. Nature. 2018;555:662–6.
doi: 10.1038/nature26137
Vriens J, Owsianik G, Hofmann T, Philipp SE, Stab J, Chen X, et al. TRPM3 is a nociceptor channel involved in the detection of noxious heat. Neuron. 2011;70:482–94.
doi: 10.1016/j.neuron.2011.02.051