CLINICAL AND MOLECULAR STUDIES OF ACHONDROPLASIS

本研究有三个具体目标：1）识别和 软骨发育不全发病和死亡原因的特征， 2)分子遗传学研究旨在确定 导致软骨发育不全和相关疾病的突变， 受影响个体的表型，以及3）分子遗传学研究 旨在鉴定其他FGFR3疾病中的突变。分子 我们实验室的遗传学研究已经确定， 软骨发育不全的散发病例遗传自父亲 38例中38例染色体异常。父亲年龄大可能在 在该位点观察到高突变率。患者的DNA研究 软骨发育不全但没有常见的软骨发育不全 突变，已经确定了一个额外的FGFR3突变，K650N，在两个， 患者其他患有软骨发育不全的患者没有明显的 FGFR3突变这些发现支持了先前的推测， 可能是软骨发育不全的遗传异质性。一种新发现 骨骼发育不良，伴严重生长迟缓、智力迟钝 和黑棘皮病，已经发现是由特定的FGFR 3 突变，K650M。到目前为止，已在3例患者中发现该突变， 这个phenotype。正在努力进一步确定临床 表型和阐明的疾病引起的发病机制， K650M突变。与NICHD的Jeffrey Baron博士合作研究 已经确定了与全身性短纤维化相关的FGFR3改变， 身材.迄今为止，在5名患者中发现了这种改变， 预测会改变已知的剪接位点。矮小症的发病机制 至少部分原因是由于这一变化，目前正在调查中。

This study has three specific aims: 1) the identification and characterization of causes of morbidity and mortality in achondroplasia, 2) molecular genetic studies designed to identify correlations between mutations which cause achondroplasia and related disorders and the phenotypes of affected individuals, and 3) molecular genetic studies designed to identify mutations in other FGFR3 disorders. Molecular genetic studies in our lab have determined that the mutated allele in sporadic cases of achondroplasia is inherited from the paternal chromosome in 38/38 cases. Advanced paternal age may play a role in the high mutation rate observed at this site. Studies of DNA from patients with hypochondroplasia, but without the common hypochondroplasia mutation, have identified an additional FGFR3 mutation, K650N, in two patients. Other patients with hypochondroplasia have not had demonstrable FGFR3 mutations These findings support previous speculation that there may be genetic heterogeneity in hypochondroplasia. A newly identified skeletal dysplasia, with profound growth retardation, mental retardation and acanthosis nigricans, has been found to result from a specific FGFR3 mutation, K650M. To date, the mutation has been found in 3 patients with this phenotype. Efforts are underway to further define the clinical phenotype and elucidate the pathogenesis of the disorder caused by the K650M mutation. Collaborative studies with Dr. Jeffrey Baron of NICHD have identified an FGFR3 alteration associated with generalized short stature. This alteration, which has been found in 5 patients to date, is predicted to alter a known splice site. The pathogenesis of short stature resulting, at least in part, from this alteration is under investigation.