title: Alterations in the ankyrin domain of TRPV4 cause congenital distal SMA, scapuloperoneal SMA and HMSN2C.
abstract: Spinal muscular atrophies (SMA, also known as hereditary motor neuropathies) and hereditary motor and sensory neuropathies (HMSN) are clinically and genetically heterogeneous disorders of the peripheral nervous system. Here we report that mutations in the TRPV4 gene cause congenital distal SMA, scapuloperoneal SMA, HMSN 2C. We identified three missense substitutions (R269H, R315W and R316C) affecting the intracellular N-terminal ankyrin domain of the TRPV4 ion channel in five families. Expression of mutant TRPV4 constructs in cells from the HeLa line revealed diminished surface localization of mutant proteins. In addition, TRPV4-regulated Ca(2+) influx was substantially reduced even after stimulation with 4alphaPDD, a TRPV4 channel-specific agonist, and with hypo-osmotic solution. In summary, we describe a new hereditary channelopathy caused by mutations in TRPV4 and present evidence that the resulting substitutions in the N-terminal ankyrin domain affect channel maturation, leading to reduced surface expression of functional TRPV4 channels.
authors.affiliation: Institute of Human Genetics, Medical University of Graz, Austria. michaela.auergrumbach@medunigraz.at
authors.forename: Michaela
authors.initials: M
authors.lastname: Auer-Grumbach
authors.forename: Andrea
authors.initials: A
authors.lastname: Olschewski
authors.forename: Lea
authors.initials: L
authors.lastname: Papić
authors.forename: Hannie
authors.initials: H
authors.lastname: Kremer
authors.forename: Meriel E
authors.initials: ME
authors.lastname: McEntagart
authors.forename: Sabine
authors.initials: S
authors.lastname: Uhrig
authors.forename: Carina
authors.initials: C
authors.lastname: Fischer
authors.forename: Eleonore
authors.initials: E
authors.lastname: Fröhlich
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Bálint
authors.forename: Bi
authors.initials: B
authors.lastname: Tang
authors.forename: Heimo
authors.initials: H
authors.lastname: Strohmaier
authors.forename: Hanns
authors.initials: H
authors.lastname: Lochmüller
authors.forename: Beate
authors.initials: B
authors.lastname: Schlotter-Weigel
authors.forename: Jan
authors.initials: J
authors.lastname: Senderek
authors.forename: Angelika
authors.initials: A
authors.lastname: Krebs
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Dick
authors.forename: Richard
authors.initials: R
authors.lastname: Petty
authors.forename: Cheryl
authors.initials: C
authors.lastname: Longman
authors.forename: Neil E
authors.initials: NE
authors.lastname: Anderson
authors.forename: George W
authors.initials: GW
authors.lastname: Padberg
authors.forename: Helenius J
authors.initials: HJ
authors.lastname: Schelhaas
authors.forename: Conny M A
authors.initials: CM
authors.lastname: van Ravenswaaij-Arts
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Pieber
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Crosby
authors.forename: Christian
authors.initials: C
authors.lastname: Guelly
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D017089:Ankyrin Repeat; D002118:Calcium / Q000378:metabolism; D006367:HeLa Cells; D015417:Hereditary Sensory and Motor Neuropathy / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D007150:Immunohistochemistry; D042541:Intracellular Space / Q000378:metabolism; D015640:Ion Channel Gating; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009134:Muscular Atrophy, Spinal / Q000150:complications / Q000151:congenital* / Q000235:genetics* / Q000503:physiopathology; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D009995:Osmosis; D050916:TRPV Cation Channels / Q000737:chemistry* / Q000235:genetics*; D014162:Transfection
chemical_list: D050505:Mutant Proteins; D050916:TRPV Cation Channels; C416986:TRPV4 protein, human; D002118:Calcium