Alterations in the ankyrin domain of TRPV4 cause congenital distal SMA, scapuloperoneal SMA and HMSN2C

Michaela Auer-Grumbach*, Andrea Olschewski, Lea Papic, Hannie Kremer, Meriel E. McEntagart, Sabine Uhrig, Carina Fischer, Eleonore Froehlich, Zoltan Balint, Bi Tang, Heimo Strohmaier, Hanns Lochmueller, Beate Schlotter-Weigel, Jan Senderek, Angelika Krebs, Katherine J. Dick, Richard Petty, Cheryl Longman, Neil E. Anderson, George W. PadbergHelenius J. Schelhaas, Conny M. A. van Ravenswaaij-Arts, Thomas R. Pieber, Andrew H. Crosby, Christian Guelly

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

    185 Citations (Scopus)

    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 4. PDD, 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.

    Original languageEnglish
    Pages (from-to)160-U96
    Number of pages7
    JournalNature Genetics
    Volume42
    Issue number2
    DOIs
    Publication statusPublished - Feb-2010

    Keywords

    • SPINAL MUSCULAR-ATROPHY
    • CATION CHANNEL
    • REPEAT DOMAIN
    • TRAFFICKING
    • LOCALIZATION
    • SENSITIVITY
    • DISEASE
    • BIND
    • MICE

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