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.
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Acknowledgements
We thank the families involved in this research and are grateful to Hayley Mountford and Greta Gillies for assistance with patient samples. We thank John Bateman for collagen analysis in BDCS1. Skin fibroblasts from BDCS3 were obtained from the Cell Line and DNA Biobank from patients affected by genetic diseases (G.Gaslini Institute), Telethon Network of Genetic Biobank (Project GTB07001A). This work was funded in part by National Health and Medical Research Council Australia Program Grant 490037 to DJA and MB. KRS is supported by a PhD scholarship funded by the Pratt Foundation. MB is supported by an ARC Future Fellowship (FT100100764). MBD is supported by an NHMRC Practitioner Fellowship (546452) and PJL is supported by an NHMRC Career Development Fellowship (APP1032364). This work was made possible through Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS.
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Wilson, G., Sunley, J., Smith, K. et al. Mutations in SH3PXD2B cause Borrone dermato-cardio-skeletal syndrome. Eur J Hum Genet 22, 741–747 (2014). https://doi.org/10.1038/ejhg.2013.229
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DOI: https://doi.org/10.1038/ejhg.2013.229
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