WNT5A mutations in patients with autosomal dominant Robinow syndrome

Anthony D. Person, Soraya Beiraghi, Christine M. Sieben, Spencer Hermanson, Ann N. Neumann, Mara E. Robu, J. Robert Schleiffarth, Charles J. Billington, Hans Van Bokhoven, Jeannette M. Hoogeboom, Juliana F. Mazzeu, Anna Petryk, Lisa A. Schimmenti, Han G. Brunner, Stephen C Ekker, Jamie L. Lohr

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131 Scopus citations

Abstract

Robinow syndrome is a skeletal dysplasia with both autosomal dominant and autosomal recessive inheritance patterns. It is characterized by short stature, limb shortening, genital hypoplasia, and craniofacial abnormalities. The etiology of dominant Robinow syndrome is unknown; however, the phenotypically more severe autosomal recessive form of Robinow syndrome has been associated with mutations in the orphan tyrosine kinase receptor, ROR2, which has recently been identified as a putative WNT5A receptor. Here, we show that two different missense mutations in WNT5A, which result in amino acid substitutions of highly conserved cysteines, are associated with autosomal dominant Robinow syndrome. One mutation has been found in all living affected members of the original family described by Meinhard Robinow and another in a second unrelated patient. These missense mutations result in decreased WNT5A activity in functional assays of zebrafish and Xenopus development. This work suggests that a WNT5A/ROR2 signal transduction pathway is important in human craniofacial and skeletal development and that proper formation and growth of these structures is sensitive to variations in WNT5A function.

Original languageEnglish (US)
Pages (from-to)327-337
Number of pages11
JournalDevelopmental Dynamics
Volume239
Issue number1
DOIs
StatePublished - Jan 2010

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Keywords

  • Robinow syndrome
  • Ror2
  • Wnt5a

ASJC Scopus subject areas

  • Developmental Biology

Cite this

Person, A. D., Beiraghi, S., Sieben, C. M., Hermanson, S., Neumann, A. N., Robu, M. E., Schleiffarth, J. R., Billington, C. J., Van Bokhoven, H., Hoogeboom, J. M., Mazzeu, J. F., Petryk, A., Schimmenti, L. A., Brunner, H. G., Ekker, S. C., & Lohr, J. L. (2010). WNT5A mutations in patients with autosomal dominant Robinow syndrome. Developmental Dynamics, 239(1), 327-337. https://doi.org/10.1002/dvdy.22156