Institute of Biology and Medical Genetics, 1st Faculty of Medicine and General Teaching Hospital, Charles University in Prague, Prague, Czech Republic.
Gene. 2012 Jan 10;491(2):123-7. doi: 10.1016/j.gene.2011.10.011. Epub 2011 Oct 14.
The aim of the study was to analyze frequency of SHOX gene defects and selected dysmorphic signs in patients of both idiopathic short stature (ISS) and Léri-Weill dyschondrosteosis (LWD), all derived from the Czech population. Overall, 98 subjects were analyzed in the study. Inclusion criteria were the presence of short stature (-2.0 SD), in combination with at least one of the selected dysmorphic signs for the ISS+ group; and the presence of Madelung deformity, without positive karyotyping for the LWD+ group. Each proband was analyzed by use of P018 MLPA kit, which covers SHOX and its regulatory sequences. Additionally, mutational analysis was done of the coding portions of the SHOX. Both extent and breakpoint localizations in the deletions/duplications found were quite variable. Some PAR1 rearrangements were detected, without obvious phenotypic association. In the ISS+ group, MLPA analysis detected four PAR1 deletions associated with a SHOX gene defect, PAR1 duplication with an ambiguous effect, and two SHOX mutations (13.7%). In the LWD+ group, MLPA analysis detected nine deletions in PAR1 region, with a deleterious effect on SHOX, first reported case of isolated SHOX enhancer duplication, and SHOX mutation (68.8%). In both ISS+ and LWD+ groups were positivity associated with a disproportionately short stature; in the ISS+ group, in combination with muscular hypertrophy. It seems that small PAR1 rearrangements might be quite frequent in the population. Our study suggests disproportionateness, especially in combination with muscular hypertrophy, as relevant indicators of ISS to be the effect of SHOX defect.
本研究的目的是分析 SHOX 基因缺陷和特发性身材矮小（ISS）和 Léri-Weill 软骨发育不全（LWD）患者中特定的发育不良体征的频率，这些患者均来自捷克人群。本研究共分析了 98 例患者。纳入标准为存在身材矮小（-2.0SD），同时伴有 ISS+组中至少一种特定的发育不良体征；以及存在 Madelung 畸形，LWD+组核型检查结果为阴性。每个先证者均使用 P018 MLPA 试剂盒进行分析，该试剂盒涵盖 SHOX 及其调控序列。此外，还对 SHOX 的编码部分进行了突变分析。发现的缺失/重复的范围和断点定位非常多变。检测到一些 PAR1 重排，但与明显的表型无关。在 ISS+组中，MLPA 分析检测到与 SHOX 基因缺陷相关的四个 PAR1 缺失、具有不确定影响的 PAR1 重复以及两个 SHOX 突变（13.7%）。在 LWD+组中，MLPA 分析检测到 PAR1 区域的九个缺失，对 SHOX 具有有害影响，首次报道孤立的 SHOX 增强子重复病例，以及 SHOX 突变（68.8%）。在 ISS+和 LWD+组中，均与不成比例的身材矮小相关；在 ISS+组中，还与肌肉肥大相关。似乎小的 PAR1 重排可能在人群中相当普遍。我们的研究表明不成比例，特别是与肌肉肥大相结合，是 ISS 中 SHOX 缺陷的相关指标。
