A novel class of pseudoautosomal region 1 deletions downstream of SHOX is associated with Leri-Weill dyschondrosteosis
A novel class of pseudoautosomal region 1 deletions downstream of SHOX is associated with Leri-Weill dyschondrosteosis
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DOI：
10.1086/449313
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发表时间：
2005-10-01
影响因子：
9.8
通讯作者：
Heath, KE
中科院分区：
文献类型：
--
作者：
Benito-Sanz, S;Thomas, NS;Heath, KE
lei - weill软骨发育异常症（LWD）是一种假常染色体显性遗传病，其特征是不成比例的身材矮小和典型的桡骨弯曲，被称为“马德隆畸形”。在LWD和不同比例的特发性身材矮小（ISS）患者中发现SHOX突变导致SHOX单倍功能不全，而SHOX纯合缺失导致更严重的兰格中粒发育不良（LMD）。在60%的LWD病例中发现了SHOX缺陷，而在其余40%的LWD病例中，其分子基础尚不清楚。这表明在未分析的SHOX区域（如上游、基因内或下游调控序列）存在遗传异质性或突变。因此，80例LWD患者的假常染色体1区（PAR1）被排除了SHOX缺失和突变，通过使用一组新的微卫星标记来筛选缺失。我们确定了12例LWD患者，他们出现了一类新的PAR1缺失，不包括SHOX。这些缺失大小不一，至少与SHOX下游30-530 kb相似。在我们的队列中，这种类型的缺失占病例的15%。在所有情况下，缺失与表型共分离。在SHOX缺失患者和这类新的PAR1缺失患者之间没有观察到明显的表型差异。因此，我们在此提出了第二个与MD发病有关的PAR1区域的鉴定。我们的研究结果表明，在PAR1中存在SHOX转录的远端调控元件，或者存在另一个明显参与骨骼发育控制的位点。在LWD、LMD和ISS患者的突变筛查中，应该包括对这一新发现区域的缺失分析。
Leri-Weill dyschondrosteosis (LWD) is a pseudoautosomal dominant disorder characterized by disproportionate short stature and a characteristic curving of the radius, known as the "Madelung deformity." SHOX mutations resulting in SHOX haploinsufficiency have been found in LWD and in a variable proportion of patients with idiopathic short stature (ISS), whereas homozygous loss of SHOX results in the more severe Langer mesomelic dysplasia (LMD). Defects in SHOX have been identified in similar to 60% of LWD cases, whereas, in the remaining similar to 40%, the molecular basis is unknown. This suggests either genetic heterogeneity or the presence of mutations in unanalyzed regions of SHOX, such as the upstream, intragenic, or downstream regulatory sequences. Therefore, the pseudoautosomal region 1 (PAR1) of 80 patients with LWD, in whom SHOX deletions and mutations had been excluded, was screened for deletions by use of a new panel of microsatellite markers. We identified 12 patients with LWD who presented with a novel class of PAR1 deletions that did not include SHOX. The deletions were of variable size and mapped at least similar to 30-530 kb downstream of SHOX. In our cohort, this type of deletion accounted for 15% of cases. In all cases, the deletions cosegregated with the phenotype. No apparent phenotypic differences were observed between patients with SHOX deletions and those with this new class of PAR1 deletions. Thus, we present here the identification of a second PAR1 region implicated in the etiopathogenesis of MD. Our findings suggest the presence of distal regulatory elements of SHOX transcription in PAR1 or, alternatively, the existence of an additional locus apparently involved in the control of skeletal development. Deletion analysis of this newly identified region should be included in the mutation screening of patients with LWD, LMD, and ISS.