The newest TRP channelopathy: Gain of function TRPM3 mutations cause epilepsy and intellectual disability

References

• Montell C, Birnbaumer L, Flockerzi V. The TRP channels, a remarkably functional family. Cell. 2002;108(5):595–598.
   PubMed Web of Science ®Google Scholar
• Ramsey IS, Delling M, Clapham DE. An introduction to TRP channels. Annu Rev Physiol. 2006;68(1):619–647.
   PubMedGoogle Scholar
• Ashcroft F. Ion Channels and Disease. 1st ed. Academic Press; 1999.
   Google Scholar
• Nilius B, Owsianik G. Transient receptor potential channelopathies. Pflugers Arch. 2010;460(2):437–450.
   PubMed Web of Science ®Google Scholar
• Kremeyer B, Lopera F, Cox JJ, et al. A gain-of-function mutation in TRPA1 causes familial episodic pain syndrome. Neuron. 2010;66(5):671–680.
   PubMed Web of Science ®Google Scholar
• Van Genderen MM, Bijveld MM, Claassen YB, et al. Mutations in TRPM1 are a common cause of complete congenital stationary night blindness. Am J Hum Genet. 2009;85(5):730–736.
   PubMed Web of Science ®Google Scholar
• Audo I, Kohl S, Leroy BP, et al. TRPM1 is mutated in patients with autosomal-recessive complete congenital stationary night blindness. Am J Hum Genet. 2009;85(5):720–729.
   PubMed Web of Science ®Google Scholar
• Li Z, Sergouniotis PI, Michaelides M, et al. Recessive mutations of the gene TRPM1 abrogate ON bipolar cell function and cause complete congenital stationary night blindness in humans. Am J Hum Genet. 2009;85(5):711–719.
   PubMed Web of Science ®Google Scholar
• Bellone RR, Brooks SA, Sandmeyer L, et al. Differential gene expression of TRPM1, the potential cause of congenital stationary night blindness and coat spotting patterns (LP) in the Appaloosa horse (Equus caballus). Genetics. 2008;179(4):1861–1870.
   PubMed Web of Science ®Google Scholar
• Walder RY, Landau D, Meyer P, et al. Mutation of TRPM6 causes familial hypomagnesemia with secondary hypocalcemia. Nat Genet. 2002;31(2):171–174.
   PubMed Web of Science ®Google Scholar
• Schlingmann KP, Weber S, Peters M, et al. Hypomagnesemia with secondary hypocalcemia is caused by mutations in TRPM6, a new member of the TRPM gene family. Nat Genet. 2002;31(2):166–170.
   PubMed Web of Science ®Google Scholar
• Suzuki Y, Chitayat D, Sawada H, et al. TRPV6 variants interfere with maternal-fetal calcium transport through the placenta and cause transient Neonatal Hyperparathyroidism. Am J Hum Genet. 2018;102(6):1104–1114.
   PubMed Web of Science ®Google Scholar
• Burren CP, Caswell R, Castle B, et al. TRPV6 compound heterozygous variants result in impaired placental calcium transport and severe undermineralization and dysplasia of the fetal skeleton. Am J Med Genet A. 2018;176(9):1950–1955.
   PubMed Web of Science ®Google Scholar
• Masamune A, Kotani H, Sorgel FL, et al. Variants that affect function of calcium channel TRPV6 are associated with early-onset Chronic Pancreatitis. Gastroenterology. 2020;158(1626–1641):e1628.
   Google Scholar
• Suzuki Y, Pasch A, Bonny O, et al. Gain-of-function haplotype in the epithelial calcium channel TRPV6 is a risk factor for renal calcium stone formation. Hum Mol Genet. 2008;17(11):1613–1618.
   PubMed Web of Science ®Google Scholar
• Oddsson A, Sulem P, Helgason H, et al. Common and rare variants associated with kidney stones and biochemical traits. Nat Commun. 2015;6(1):7975.
   PubMedGoogle Scholar
• Wang L, Holmes RP, Peng JB. The L530R variation associated with recurrent kidney stones impairs the structure and function of TRPV5. Biochem Biophys Res Commun. 2017;492(3):362–367.
   PubMed Web of Science ®Google Scholar
• Winn MP, Conlon PJ, Lynn KL, et al. A mutation in the TRPC6 cation channel causes familial focal segmental glomerulosclerosis. Science. 2005;308(5729):1801–1804.
   PubMed Web of Science ®Google Scholar
• Wu G, Somlo S. Molecular genetics and mechanism of autosomal dominant polycystic kidney disease. Mol Genet Metab. 2000;69(1):1–15.
   PubMed Web of Science ®Google Scholar
• Lin Z, Chen Q, Lee M, et al. Exome sequencing reveals mutations in TRPV3 as a cause of Olmsted syndrome. Am J Hum Genet. 2012;90(3):558–564.
   PubMed Web of Science ®Google Scholar
• Wang H, Xu Z, Lee BH, et al. Gain-of-function mutations in TRPM4 activation gate cause progressive symmetric Erythrokeratodermia. J Invest Dermatol. 2019;139(5):1089–1097.
   PubMed Web of Science ®Google Scholar
• Kruse M, Schulze-Bahr E, Corfield V, et al. Impaired endocytosis of the ion channel TRPM4 is associated with human progressive familial heart block type I. J Clin Invest. 2009;119(9):2737–2744.
   PubMed Web of Science ®Google Scholar
• Bassi MT, Manzoni M, Monti E, et al. Cloning of the gene encoding a novel integral membrane protein, mucolipidin-and identification of the two major founder mutations causing mucolipidosis type IV. Am J Hum Genet. 2000;67(5):1110–1120.
   PubMed Web of Science ®Google Scholar
• Sun M, Goldin E, Stahl S, et al. Mucolipidosis type IV is caused by mutations in a gene encoding a novel transient receptor potential channel. Hum Mol Genet. 2000;9(17):2471–2478.
   PubMed Web of Science ®Google Scholar
• Hermosura MC, Nayakanti H, Dorovkov MV, et al. A TRPM7 variant shows altered sensitivity to magnesium that may contribute to the pathogenesis of two Guamanian neurodegenerative disorders. Proc Natl Acad Sci U S A. 2005;102(32):11510–11515.
   PubMed Web of Science ®Google Scholar
• Hermosura MC, Cui AM, Go RC, et al. Altered functional properties of a TRPM2 variant in Guamanian ALS and PD. Proc Natl Acad Sci U S A. 2008;105(46):18029–18034.
   PubMed Web of Science ®Google Scholar
• Grigelioniene G, Geiberger S, Horemuzova E, et al. Autosomal dominant brachyolmia in a large Swedish family: phenotypic spectrum and natural course. Am J Med Genet A. 2014;164A(7):1635–1641.
   PubMedGoogle Scholar
• Krakow D, Vriens J, Camacho N, et al. Mutations in the gene encoding the calcium-permeable ion channel TRPV4 produce spondylometaphyseal dysplasia, Kozlowski type and metatropic dysplasia. Am J Hum Genet. 2009;84(3):307–315.
   PubMed Web of Science ®Google Scholar
• Fiorillo C, Moro F, Brisca G, et al. TRPV4 mutations in children with congenital distal spinal muscular atrophy. Neurogenetics. 2012;13(3):195–203.
   PubMed Web of Science ®Google Scholar
• Deng HX, Klein CJ, Yan J, et al. Scapuloperoneal spinal muscular atrophy and CMT2C are allelic disorders caused by alterations in TRPV4. Nat Genet. 2010;42(2):165–169.
   PubMed Web of Science ®Google Scholar
• Garcia-Elias A, Mrkonjic S, Jung C, et al. The TRPV4 channel. Handb Exp Pharmacol. 2014;222:293–319.
   PubMedGoogle Scholar
• Nilius B, Voets T. The puzzle of TRPV4 channelopathies. EMBO Rep. 2013;14(2):152–163.
   PubMed Web of Science ®Google Scholar
• Tian W, Fu Y, Garcia-Elias A, et al. A loss-of-function nonsynonymous polymorphism in the osmoregulatory TRPV4 gene is associated with human hyponatremia. Proc Natl Acad Sci U S A. 2009;106:14034–14039.
   PubMed Web of Science ®Google Scholar
• Vriens J, Voets T. Sensing the heat with TRPM3. Pflugers Arch. 2018;470(5):799–807.
   PubMed Web of Science ®Google Scholar
• Dyment DA, Terhal PA, Rustad CF, et al. De novo substitutions of TRPM3 cause intellectual disability and epilepsy. Eur J Hum Genet. 2019;27(10):1611–1618.
   PubMed Web of Science ®Google Scholar
• Van Hoeymissen E, Held K, Freitas ACN, et al. Gain of channel function and modified gating properties in TRPM3 mutants causing intellectual disability and epilepsy. eLife. 2020;9:e57190.
   PubMed Web of Science ®Google Scholar
• Zhao S, Yudin Y, Rohacs T. Disease-associated mutations in the human TRPM3 render the channel overactive via two distinct mechanisms. Elife. 2020;9:e55634.
   PubMed Web of Science ®Google Scholar
• Humphray S, Oliver K, Hunt A, et al. DNA sequence and analysis of human chromosome 9. Nature. 2004;429(6990):369–374.
   PubMed Web of Science ®Google Scholar
• Oberwinkler J, Lis A, Giehl KM, et al. Alternative splicing switches the divalent cation selectivity of TRPM3 channels. J Biol Chem. 2005;280(23):22540–22548.
   PubMed Web of Science ®Google Scholar
• Oberwinkler J, Philipp SE. Trpm3. Handb Exp Pharmacol. 2014;222:427–459.
   PubMedGoogle Scholar
• Lee N, Chen J, Sun L, et al. Expression and characterization of human transient receptor potential melastatin 3 (hTRPM3). J Biol Chem. 2003;278(23):20890–20897.
   PubMed Web of Science ®Google Scholar
• Grimm C, Kraft R, Sauerbruch S, et al. Molecular and functional characterization of the melastatin-related cation channel TRPM3. J Biol Chem. 2003;278(24):21493–21501.
   PubMed Web of Science ®Google Scholar
• Badheka D, Borbiro I, Rohacs T. Transient receptor potential melastatin 3 is a phosphoinositide-dependent ion channel. J Gen Physiol. 2015;146(1):65–77.
   PubMed Web of Science ®Google Scholar
• Toth BI, Konrad M, Ghosh D, et al. Regulation of the transient receptor potential channel TRPM3 by phosphoinositides. J Gen Physiol. 2015;146(1):51–63.
   PubMed Web of Science ®Google Scholar
• Vriens J, Held K, Janssens A, et al. Opening of an alternative ion permeation pathway in a nociceptor TRP channel. Nat Chem Biol. 2014;10:188.
   PubMed Web of Science ®Google Scholar
• Held K, Kichko T, De Clercq K, et al. Activation of TRPM3 by a potent synthetic ligand reveals a role in peptide release. Proc Natl Acad Sci U S A. 2015;112(11):E1363–1372.
   PubMed Web of Science ®Google Scholar
• Vriens J, Owsianik G, Hofmann T, et al. TRPM3 is a nociceptor channel involved in the detection of noxious heat. Neuron. 2011;70(3):482–494.
   PubMed Web of Science ®Google Scholar
• Vangeel L, Benoit M, Miron Y, et al. Functional expression and pharmacological modulation of TRPM3 in human sensory neurons. Br J Pharmacol. 2020;177(12):2683–2695.
   PubMed Web of Science ®Google Scholar
• Vandewauw I, De Clercq K, Mulier M, et al. A TRP channel trio mediates acute noxious heat sensing. Nature. 2018;555(7698):662–666.
   PubMed Web of Science ®Google Scholar
• Mulier M, Van Ranst N, Corthout N, et al. Upregulation of TRPM3 in nociceptors innervating inflamed tissue. Elife. 2020;9:e61103.
   PubMed Web of Science ®Google Scholar
• Su S, Yudin Y, Kim N, et al. TRPM3 channels play roles in heat hypersensitivity and spontaneous pain after nerve injury. J Neurosci. in press.
   Web of Science ®Google Scholar
• Becker A, Mannebach S, Mathar I, et al. Control of insulin release by Transient Receptor Potential Melastatin 3 (TRPM3) ion channels. Cell Physiol Biochem. 2020;54:1115–1131.
   PubMedGoogle Scholar
• Hoffmann A, Grimm C, Kraft R, et al. TRPM3 is expressed in sphingosine-responsive myelinating oligodendrocytes. J Neurochem. 2010;114(3):654–665.
   PubMed Web of Science ®Google Scholar
• Zamudio-Bulcock PA, Everett J, Harteneck C, et al. Activation of steroid-sensitive TRPM3 channels potentiates glutamatergic transmission at cerebellar Purkinje neurons from developing rats. J Neurochem. 2011;119(3):474–485.
   PubMed Web of Science ®Google Scholar
• Ragozzino FJ, Arnold RA, Fenwick AJ, et al. TRPM3 expression and control of glutamate release from primary vagal afferent neurons. J Neurophysiol. 2021;125(1):199–210.
   PubMed Web of Science ®Google Scholar
• Straub I, Krugel U, Mohr F, et al. Flavanones that selectively inhibit TRPM3 attenuate thermal nociception in vivo. Mol Pharmacol. 2013;84(5):736–750.
   PubMed Web of Science ®Google Scholar
• Krugel U, Straub I, Beckmann H, et al. Primidone inhibits TRPM3 and attenuates thermal nociception in vivo. Pain. 2017;158(5):856–867.
   PubMed Web of Science ®Google Scholar
• Quallo T, Alkhatib O, Gentry C, et al. G protein βγ subunits inhibit TRPM3 ion channels in sensory neurons. Elife. 2017;6:e26138.
   PubMed Web of Science ®Google Scholar
• Badheka D, Yudin Y, Borbiro I, et al. Inhibition of transient receptor potential Melastatin 3 ion channels by G-protein βγ subunits. Elife. 2017;6:e26147.
   PubMed Web of Science ®Google Scholar
• Dembla S, Behrendt M, Mohr F, et al. Anti-nociceptive action of peripheral mu-opioid receptors by Gβγ protein-mediated inhibition of TRPM3 channels. Elife. 2017;6:e26280.
   PubMed Web of Science ®Google Scholar
• Behrendt M, Gruss F, Enzeroth R, et al. The structural basis for an on-off switch controlling Gβγ-mediated inhibition of TRPM3 channels. Proc Natl Acad Sci U S A. 2020;117(46):29090–29100.
   PubMed Web of Science ®Google Scholar
• Alkhatib O, Da Costa R, Gentry C, et al. Promiscuous G-protein-coupled receptor inhibition of transient receptor potential Melastatin 3 Ion channels by Gβγ subunits. J Neurosci. 2019;39(40):7840–7852.
   PubMed Web of Science ®Google Scholar
• Mbuba CK, Ngugi AK, Newton CR, et al. The epilepsy treatment gap in developing countries: a systematic review of the magnitude, causes, and intervention strategies. Epilepsia. 2008;49(9):1491–1503.
   PubMed Web of Science ®Google Scholar
• Sisodiya SM. Malformations of cortical development: burdens and insights from important causes of human epilepsy. Lancet Neurol. 2004;3:29–38.
   PubMed Web of Science ®Google Scholar
• Duncan JS, Sander JW, Sisodiya SM, et al. Adult epilepsy. Lancet. 2006;367(9516):1087–1100.
   PubMed Web of Science ®Google Scholar
• Thakran S, Guin D, Singh P, et al. Genetic landscape of common Epilepsies: advancing towards precision in treatment. Int J Mol Sci. 2020;21(20):7784.
   Web of Science ®Google Scholar
• Muona M, Berkovic SF, Dibbens LM, et al. A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy. Nat Genet. 2015;47(1):39.
   PubMed Web of Science ®Google Scholar
• Wengert ER, Patel MK. The role of the persistent sodium current in Epilepsy. Epilepsy Curr. 2020;21(1):40–47.
   PubMed Web of Science ®Google Scholar
• D’Adamo MC, Liantonio A, Conte E, et al. Ion channels involvement in neurodevelopmental disorders. Neuroscience. 2020;440:337–359.
   PubMed Web of Science ®Google Scholar
• Schroeder BC, Kubisch C, Stein V, et al. Moderate loss of function of cyclic-AMP-modulated KCNQ2/KCNQ3 K+ channels causes epilepsy. Nature. 1998;396(6712):687–690.
   PubMed Web of Science ®Google Scholar
• De Sainte Agathe J-M, Van-Gils J, Lasseaux E, et al. Confirmation and expansion of the phenotype associated with the recurrent p.Val837Met variant in TRPM3. Eur J Med Genet. 2020;63(8):103942.
   PubMed Web of Science ®Google Scholar
• Hughes S, Pothecary CA, Jagannath A, et al. Profound defects in pupillary responses to light in TRPM-channel null mice: a role for TRPM channels in non-image-forming photoreception. Eur J Neurosci. 2012;35(1):34–43.
   PubMed Web of Science ®Google Scholar
• Bennett TM, Mackay DS, Siegfried CJ, et al. Mutation of the melastatin-related cation channel, TRPM3, underlies inherited cataract and glaucoma. PloS One. 2014;9(8):e104000.
   Web of Science ®Google Scholar
• Zhou Y, Bennett TM, Shiels A. Mutation of the TRPM3 cation channel underlies progressive cataract development and lens calcification associated with pro-fibrotic and immune cell responses. Faseb J. 2021;35:e21288.
   PubMed Web of Science ®Google Scholar
• Diaz-Franulic I, Poblete H, Mino-Galaz G, et al. Allosterism and structure in thermally activated transient receptor potential channels. Annu Rev Biophys. 2016;45(1):371–398.
   PubMedGoogle Scholar
• Hofmann L, Wang H, Zheng W, et al. The S4–S5 linker–gearbox of TRP channel gating. Cell Calcium. 2017;67:156–165.
   PubMed Web of Science ®Google Scholar
• Huang Y, Fliegert R, Guse AH, et al. A structural overview of the ion channels of the TRPM family. Cell Calcium. 2020;85:102111.
   PubMed Web of Science ®Google Scholar
• Yin Y, Wu M, Zubcevic L, et al. Structure of the cold-and menthol-sensing ion channel TRPM8. Science. 2018;359(6372):237–241.
   PubMed Web of Science ®Google Scholar
• Drews A, Mohr F, Rizun O, et al. Structural requirements of steroidal agonists of transient receptor potential melastatin 3 (TRPM 3) cation channels. Br J Pharmacol. 2014;171(4):1019–1032.
   PubMed Web of Science ®Google Scholar
• Colquhoun D. Binding, gating, affinity and efficacy: the interpretation of structure-activity relationships for agonists and of the effects of mutating receptors. Br J Pharmacol. 1998;125(5):924–947.
   PubMed Web of Science ®Google Scholar
• Rohacs T, Lopes CM, Michailidis I, et al. PI(4,5)P2 regulates the activation and desensitization of TRPM8 channels through the TRP domain. Nat Neurosci. 2005;8(5):626–634.
   PubMed Web of Science ®Google Scholar
• Zhang F, Jara-Oseguera A, Chang T-H, et al. Heat activation is intrinsic to the pore domain of TRPV1. Proc Natl Acad Sci USA. 2018;115:E317–E324
   PubMed Web of Science ®Google Scholar
• Singh AK, McGoldrick LL, Demirkhanyan L, et al. Structural basis of temperature sensation by the TRP channel TRPV3. Nat Struct Mol Biol. 2019;26(11):994–998.
   PubMed Web of Science ®Google Scholar
• Held K, Gruss F, Aloi VD, et al. Mutations in the voltage-sensing domain affect the alternative ion permeation pathway in the TRPM3 channel. J Physiol. 2018;596:2413–2432.
   PubMed Web of Science ®Google Scholar