Wilson Gabrielle R, Sunley Jasmine, Smith Katherine R, Pope Kate, Bromhead Catherine J, Fitzpatrick Elizabeth, Di Rocco Maja, van Steensel Maurice, Coman David J, Leventer Richard J, Delatycki Martin B, Amor David J, Bahlo Melanie, Lockhart Paul J
1] Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, The Royal Children's Hospital, Flemington Road, Melbourne, VIC, Australia [2] Department of Paediatrics, The University of Melbourne, Melbourne, VIC, Australia.
Bioinformatics Division, The Walter and Eliza Hall Institute, Melbourne, VIC, Australia.
Eur J Hum Genet. 2014 Jun;22(6):741-7. doi: 10.1038/ejhg.2013.229. Epub 2013 Oct 9.
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.
博龙皮肤-心脏-骨骼（BDCS）综合征是一种严重的进行性常染色体隐性疾病，其特征为面容粗糙、皮肤增厚、聚合性痤疮、面部畸形、脊柱异常和二尖瓣脱垂。我们鉴定出一个近亲家族，该家族中有一名临床诊断为BDCS的儿童。对这个家族（BDCS1）进行连锁分析，确定了五个同源纯合区域，最大对数优势分数为1.75。对最初定义BDCS的家族（BDCS3）进行连锁分析，在染色体5q35.1处发现了一个重叠的连锁峰。序列分析在BDCS1和BDCS3中鉴定出两个不同的纯合突变，影响编码含SH3和PX结构域蛋白2B（SH3PXD2B）的基因，该基因定位于5q35.1。对来自两个家族中受影响个体的患者成纤维细胞进行蛋白质免疫印迹分析，结果显示SH3PXD2B完全缺失。对另一个已发表的BDCS家族（BDCS2）进行纯合性定位和序列分析，排除了SH3PXD2B。功能性足体的形成需要SH3PXD2B，最近研究表明，13个患有弗兰克-特哈综合征（FTHS）的家族中有7个家族的病因是SH3PXD2B功能缺失突变。FTHS和BDCS有一些重叠的临床特征；因此，我们的结果表明，一部分BDCS和FTHS病例是等位基因所致。在足体形成和调节中起作用的其他基因的突变可能是SH3PXD2B突变阴性的BDSC/FTHS患者的病因。
