Clinical and Molecular Studies of Malformations

该实验室使用一种转化研究方法来研究人类畸形。在临床领域，我们实施了几项临床研究方案来评估多效性发育异常的严重程度、畸形范围和自然病史。我们使用临床评估，包括病史和体检，影像研究包括X光、超声波和断层扫描，以及EEG、肺功能测试等，以确定功能和结构异常的特征。在选定的病例中，我们也进行外科治疗，如果它们能提供临床益处，并可以促进我们对正在研究的疾病的了解。我们目前正在研究的一些疾病包括Pallister-Hall、Greig头多发性综合征、McKusick Kaufman、Proteus、Bardet-Biedl、Lenz小眼炎和眼面部心脏综合征。 我们使用现代分子生物学的工具来确定这些疾病的分子发病机制。这些包括定位克隆、微阵列表达和微阵列CGH分析、评估细胞生物学功能和基因产品异常的细胞和组织培养研究，以及人类遗传病动物模型(小鼠和斑马鱼)的建立和分析。 利用这些技术，我们已经阐明了Pallister-Hall、McKusick-Kaufman、Lenz小眼炎和眼面部心脏起搏综合征的病因。此外，我们通过比较Pallister-Hall综合征的致病基因(GLI3)和其果蝇同源物(肘部中断)的功能，并将这些功能与150多名患者的突变相关联，证明了Pallister-Hall综合征的功能缺陷。在此过程中，我们已经确定Pallister Hall综合征的机制与Greig头多指并指综合征的机制不同。我们还在临床上重新定义了变形综合症，这是一种与肿瘤易感性有关的马赛克过度生长障碍。我们通过评估一系列35名患者和对文献中报告的所有病例进行详尽的调查来做到这一点。这使我们能够为这种疾病建立新的临床诊断标准，并描绘出一种新的疾病实体，即半增生性多发性脂肪瘤综合征。在我们对Lenz小眼症综合征的研究中，我们确定这种疾病实际上是两种不同的X连锁疾病的合并，一种形式的Lenz等位基因与眼面部心脏综合征等位，这两种疾病都是由BCOR基因突变引起的。 最后，我们正在使用动物模型来研究两种疾病，一种是Amish小头畸形综合征，我们确定这种综合征是由DNC基因突变引起的，另一种是Greig头多指并指综合征的表型。对于阿米什小头症，我们已经使用转基因技术创建了这种疾病的小鼠基因敲除模型，并正在使用遗传和生化分析研究这种疾病的病理生理学。我们还利用一家大型育种机构发现的一个零星突变体，对小鼠的Greig头多指并指表型进行了定位克隆分析。这种疾病现在已经被绘制到一个500kb的区间，候选基因正在进行测序。

The laboratory uses a translational research approach to study human malformations. In the clinical arena, we operate several clinical research protocols to assess the range of severity, spectrum of malformations, and natural history of pleiotropic developmental anomalies. We use clinical evaluations that include history and physical examination, imaging studies including radiography, ultrasound, and tomography, as well as EEG, pulmonary function testing, etc. to characterize functional and structural anomalies. In selected cases we also perform surgical treatments if they offer clinical benefit and can advance our understanding of the disease under study. Some of the disorders that we are currently studying include Pallister-Hall, Greig cephalopolysyndactyly, McKusick Kaufman, Proteus, Bardet-Biedl, Lenz microphthalmia, and Oculofaciocardiodental syndromes. We use the tools of modern molecular biology to determine the molecular pathogenesis of these disorders. These include positional cloning, microarray expression and microarray CGH analysis, cell and tissue culture studies to assess cell biologic functions and abnormalities of gene products, and the creation and analysis of animal models of human genetic disease (mouse and zebrafish). Using these techniques we have elucidated the etiology of Pallister-Hall, McKusick-Kaufman, Lenz microphthalmia and Oculofaciocardiodental syndromes. In addition, we have demonstrated the functional defect of Pallister-Hall syndrome by comparing the function of the causative gene in that disorder (GLI3) to its Drosophila homologue (cubitus interruptus) and correlating those functions with mutations in over 150 patients. In so doing, we have determined that the mechanism of Pallister Hall syndrome is distinct from that of Greig cephalopolysyndactyly syndrome. We have also clinically redefined the Proteus syndrome, a disorder of mosaic overgrowth with tumor susceptibility. We did this through evaluating a series of 35 patients and an exhaustive survey of all cases reported in the literature. This allowed us to establish new clinical diagnostic criteria for this disorder and delineate a novel disease entity, the hemihyperplasia-multiple lipomatosis syndrome. In our studies of Lenz microphthalmia syndrome we determined that this disorder is actually an amalgamation of two distinct X-linked diseases and that one form of Lenz is allelic to Oculofaciocardiodental syndrome and that both of these diseases are caused by mutations in the BCOR gene. Finally, we are using animal models to study two disorders, Amish microcephaly syndrome, which we determined to be caused by mutations in the DNC gene, and a phenocopy of Greig cephalopolysyndactyly syndrome. For Amish microcephaly, we have created a mouse knockout model of that disease using transgenic technology and are studying the pathophysiology of that disorder using genetic and biochemical analysis. We are also performing a positional cloning analysis of the Greig cephalopolysyndactyly phenotype in the mouse using a sporadic mutant identified at a large breeding facility. This disorder has now been mapped to a 500 KB interval and candidate genes are being sequenced.