Clinical and genetic studies of limb anomaly syndromes

这项研究涵盖了一系列表型，包括Pallister-Hall综合征、等位基因疾病Greig头多指并指综合征(GCPS)、McKusick-Kaufman综合征(MKS)和Bardet-Biedl综合征(BBS)。这些疾病的临床表现包括多指畸形、中枢神经系统畸形(伴有或不伴有智力低下和癫痫)、颅面畸形和内脏畸形，如肾脏畸形或先天性心脏缺陷。我们通过翻译的方法研究这些疾病，从临床开始，通过体检、包括X线片、超声波、MRI和CT扫描的成像研究对表型进行仔细的临床评估。我们已经证明，BBS和MKS都可以由同一基因的突变引起。PHS和GCPS是由GLI3基因的广泛突变引起的。一种类型的突变会导致PHS(基因中间三分之一的截断)，任何功能突变或3‘截断都会导致GCPS。GCPS表型的严重程度，特别是智力低下和学习障碍，与突变相关。缺失较大的患者有更严重的表型。我们正在鉴定一种小鼠突变体，它是额外脚趾Gli3小鼠突变体的表型复制，该突变体与Gli3以外的一个基因座连锁。我们之所以研究这种动物，是因为它应该能揭示Gli3途径中的其他基因。

This research study encompasses a range of phenotypes that include Pallister-Hall syndrome, the allelic disorder Greig cephalopolysyndactyly syndrome (GCPS), McKusick-Kaufman syndrome (MKS), and Bardet-Biedl syndrome (BBS). The clinical manifestations of these disorders include polydactyly, central nervous system malformations (with or without mental retardation and seizures), craniofacial malformations, and visceral malformations such as renal malformations or congenital heart defects. We study these disorders by a translational approach that begins in the clinic with careful clinical evaluation of the phenotypes by physical examination, imaging studies that include radiographs, ultrasound, MRI and CT scanning. We have shown that BBS and MKS can both be caused by mutations in the same gene. PHS and GCPS are caused by a wide spectrum of mutations in the GLI3 gene. One type of mutations causes PHS (truncations in the middel third of the gene) and any loss of function mutation OR 3' truncation causes GCPS. The severity of the GCPS phenotype, specifically the mental retardation and learning disability, are correlated with the mutations. Patients with larger deletions have a more severe phenotype. We are characterizing a mouse mutant that is a phenocopy of the extra toes Gli3 mouse mutant that is linked to a locus other than Gli3. We are studying this animal because it should shed light on other genes in the Gli3 pathway.