Mutations in SH3PXD2B cause Borrone dermato-cardio-skeletal syndrome

Gabrielle R. Wilson, Jasmine Sunley, Katherine R. Smith, Kate Pope, Catherine J. Bromhead, Elizabeth Fitzpatrick, Maja Di Rocco, Maurice Van Steensel, David J. Coman, Richard J. Leventer, Martin B. Delatycki, David J. Amor, Melanie Bahlo, Paul J. Lockhart

Research output: Contribution to journalArticle

Abstract

Borrone Dermato-Cardio-Skeletal (BDCS) syndrome is a severe progressive autosomal recessive disorder characterized by coarse facies, thick skin, acne conglobata, dysmorphic facies, vertebral abnormalities and mitral valve prolapse. We identified a consanguineous kindred with a child clinically diagnosed with BDCS. Linkage analysis of this family (BDCS1) identified five regions homozygous by descent with a maximum LOD score of 1.75. Linkage analysis of the family that originally defined BDCS (BDCS3) identified an overlapping linkage peak at chromosome 5q35.1. Sequence analysis identified two different homozygous mutations in BDCS1 and BDCS3, affecting the gene encoding the protein SH3 and PX domains 2B (SH3PXD2B), which localizes to 5q35.1. Western blot analysis of patient fibroblasts derived from affected individuals in both families demonstrated complete loss of SH3PXD2B. Homozygosity mapping and sequence analysis in a second published BDCS family (BDCS2) excluded SH3PXD2B. SH3PXD2B is required for the formation of functional podosomes, and loss-of-function mutations in SH3PXD2B have recently been shown to underlie 7 of 13 families with Frank-Ter Haar syndrome (FTHS). FTHS and BDCS share some overlapping clinical features; therefore, our results demonstrate that a proportion of BDCS and FTHS cases are allelic. Mutations in other gene(s) functioning in podosome formation and regulation are likely to underlie the SH3PXD2B-mutation-negative BDSC/FTHS patients.

Original languageEnglish
Pages (from-to)741-747
Number of pages7
JournalEuropean Journal of Human Genetics
Volume22
Issue number6
DOIs
Publication statusPublished - 2014

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Keywords

  • adaptor protein
  • clinical genetics; musculoskeletal abnormality
  • linkage
  • molecular genetics
  • podosome

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics
  • Medicine(all)

Cite this

Wilson, G. R., Sunley, J., Smith, K. R., Pope, K., Bromhead, C. J., Fitzpatrick, E., Di Rocco, M., Van Steensel, M., Coman, D. J., Leventer, R. J., Delatycki, M. B., Amor, D. J., Bahlo, M., & Lockhart, P. J. (2014). Mutations in SH3PXD2B cause Borrone dermato-cardio-skeletal syndrome. European Journal of Human Genetics, 22(6), 741-747. https://doi.org/10.1038/ejhg.2013.229