neurogenetics

, Volume 13, Issue 3, pp 195–203

TRPV4 mutations in children with congenital distal spinal muscular atrophy

  • Chiara Fiorillo
  • Francesca Moro
  • Giacomo Brisca
  • Guja Astrea
  • Claudia Nesti
  • Zoltán Bálint
  • Andrea Olschewski
  • Maria Chiara Meschini
  • Christian Guelly
  • Michaela Auer-Grumbach
  • Roberta Battini
  • Marina Pedemonte
  • Alessandro Romano
  • Valeria Menchise
  • Roberta Biancheri
  • Filippo M. Santorelli
  • Claudio Bruno
Original Article

DOI: 10.1007/s10048-012-0328-7

Cite this article as:
Fiorillo, C., Moro, F., Brisca, G. et al. Neurogenetics (2012) 13: 195. doi:10.1007/s10048-012-0328-7

Abstract

Inherited disorders characterized by motor neuron loss and muscle weakness are genetically heterogeneous. The recent identification of mutations in the gene encoding transient receptor potential vanilloid 4 (TRPV4) in distal spinal muscular atrophy (dSMA) prompted us to screen for TRPV4 mutations in a small group of children with compatible phenotype. In a girl with dSMA and vocal cord paralysis, we detected a new variant (p.P97R) localized in the cytosolic N-terminus of the TRPV4 protein, upstream of the ankyrin-repeat domain, where the great majority of disease-associated mutations reside. In another child with congenital dSMA, in this case associated with bone abnormalities, we detected a previously reported mutation (p.R232C). Functional analysis of the novel p.P97R mutation in a heterologous system demonstrated a loss-of-function mechanism. Protein localization studies in muscle, skin, and cultured skin fibroblasts from both patients showed normal protein expression. No TRPV4 mutations were detected in four children with dSMA without bone or vocal cord involvement. Adding to the clinical and molecular heterogeneity of TRPV4-associated diseases, our results suggest that molecular testing of the TRPV4 gene is warranted in cases of congenital dSMA with bone abnormalities and vocal cord paralysis.

Keywords

Distal SMATRPV4MutationVocal cordGenotype–phenotype correlations

Supplementary material

10048_2012_328_Fig6_ESM.jpg (83 kb)
Supplementary Figure 1

Immunofuorescence (IF) panel of muscle and skin sections from a control and patient 1 to evaluate the expression of the TRPV4 gene product. In muscle sections from both patient and control, TRPV4 is diffusely but modestly expressed in the cytosol (A, C). In skin sections (B, D) TRPV4 shows intense binding on keratinocyte layer, endothelium and nerve endings, as described [11, 22]. No significant differences can be observed between patient and control. (JPEG 83 kb)

10048_2012_328_MOESM1_ESM.tif (2.1 mb)
High Resolution Image (TIFF 2188 kb)
10048_2012_328_Fig7_ESM.jpg (52 kb)
Supplementary Figure 1

Immunofuorescence (IF) panel of muscle and skin sections from a control and patient 1 to evaluate the expression of the TRPV4 gene product. In muscle sections from both patient and control, TRPV4 is diffusely but modestly expressed in the cytosol (A, C). In skin sections (B, D) TRPV4 shows intense binding on keratinocyte layer, endothelium and nerve endings, as described [11, 22]. No significant differences can be observed between patient and control. (JPEG 83 kb)

10048_2012_328_MOESM2_ESM.tif (880 kb)
High Resolution Image (TIFF 880 kb)
10048_2012_328_Fig8_ESM.jpg (44 kb)
Supplementary Figure 1

Immunofuorescence (IF) panel of muscle and skin sections from a control and patient 1 to evaluate the expression of the TRPV4 gene product. In muscle sections from both patient and control, TRPV4 is diffusely but modestly expressed in the cytosol (A, C). In skin sections (B, D) TRPV4 shows intense binding on keratinocyte layer, endothelium and nerve endings, as described [11, 22]. No significant differences can be observed between patient and control. (JPEG 83 kb)

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Chiara Fiorillo
    • 1
  • Francesca Moro
    • 2
  • Giacomo Brisca
    • 3
  • Guja Astrea
    • 1
  • Claudia Nesti
    • 2
  • Zoltán Bálint
    • 4
    • 5
  • Andrea Olschewski
    • 4
    • 5
  • Maria Chiara Meschini
    • 2
  • Christian Guelly
    • 6
  • Michaela Auer-Grumbach
    • 7
  • Roberta Battini
    • 1
  • Marina Pedemonte
    • 3
  • Alessandro Romano
    • 8
  • Valeria Menchise
    • 9
  • Roberta Biancheri
    • 3
  • Filippo M. Santorelli
    • 1
    • 2
  • Claudio Bruno
    • 3
  1. 1.Neuromuscular UnitIRCCS Stella MarisPisaItaly
  2. 2.Molecular MedicineIRCCS Stella MarisPisaItaly
  3. 3.Department of NeuroscienceIRCCS G. GasliniGenoaItaly
  4. 4.Department of Anaesthesia and Intensive Care MedicineMedical University of GrazGrazAustria
  5. 5.Ludwig Boltzmann Institute for Lung Vascular ResearchGrazAustria
  6. 6.Centre for Medical ResearchMedical University of GrazGrazAustria
  7. 7.Institute of Human GeneticsMedical University of GrazGrazAustria
  8. 8.Department of Biological and Environmental Sciences and TechnologiesUniversity of SalentoLecceItaly
  9. 9.Institute for Biostructures and Bioimages (CNR), Molecular Biotechnology CenterUniversity of TurinTurinItaly