Zhang Honghao, Takeda Haruko, Tsuji Takehito, Kamiya Nobuhiro, Rajderkar Sudha, Louie Ke'Ale, Collier Crystal, Scott Greg, Ray Manas, Mochida Yoshiyuki, Kaartinen Vesa, Kunieda Tetsuo, Mishina Yuji
Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Michigan.
Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina.
Genesis. 2015 Sep;53(9):612-626. doi: 10.1002/dvg.22879. Epub 2015 Aug 10.
Ellis-van Creveld (EvC) syndrome (OMIM 225500) is an autosomal recessive disease characterized with chondrodysplastic dwarfism in association with abnormalities in oral cavity. Ciliary proteins EVC and EVC2 have been identified as causative genes and they play an important role on Hedgehog signal transduction. We have also identified a causative gene LIMBIN for bovine chondrodysplastic dwarfism (bcd) that is later identified as the bovine ortholog of EVC2. Here, we report generation of conventional and conditional mutant Evc2/Limbin alleles that mimics mutations found in EvC patients and bcd cattle. Resulted homozygous mice showed no ciliary localization of EVC2 and EVC and displayed reduced Hedgehog signaling activity in association with skeletal and oral defects similar to the EvC patients. Cartilage-specific disruption of Evc2/Limbin resulted in similar but milder skeletal defects, whereas osteoblast-specific disruption did not cause overt changes in skeletal system. Neural crest-specific disruption of Evc2/Limbin resulted in defective incisor growth similar to that seen in conventional knockouts; however, differentiation of amelobolasts was relatively normal in the conditional knockouts. These results showcased functions of EVC2/LIMBIN during formation of mineralized tissues. Availability of the conditional allele for this gene should facilitate further detailed analyses of the role of EVC2/LIMBIN in pathogenesis of EvC syndrome. genesis 53:612-626, 2015. © 2015 Wiley Periodicals, Inc.
埃利斯-范克里维尔德（EvC）综合征（OMIM 225500）是一种常染色体隐性疾病，其特征为软骨发育不良性侏儒症并伴有口腔异常。纤毛蛋白EVC和EVC2已被确定为致病基因，它们在刺猬信号转导中起重要作用。我们还确定了牛软骨发育不良性侏儒症（bcd）的致病基因LIMBIN，该基因后来被确定为EVC2的牛直系同源基因。在此，我们报告了常规和条件性突变Evc2/Limbin等位基因的产生，这些等位基因模拟了EvC患者和bcd牛中发现的突变。产生的纯合小鼠显示EVC2和EVC无纤毛定位，并表现出刺猬信号活性降低，伴有与EvC患者相似的骨骼和口腔缺陷。Evc2/Limbin的软骨特异性破坏导致了相似但较轻的骨骼缺陷，而成骨细胞特异性破坏未引起骨骼系统的明显变化。Evc2/Limbin的神经嵴特异性破坏导致切牙生长缺陷，类似于常规基因敲除所见；然而，在条件性基因敲除中，成釉细胞的分化相对正常。这些结果展示了EVC2/LIMBIN在矿化组织形成过程中的功能。该基因条件性等位基因的可用性应有助于进一步详细分析EVC2/LIMBIN在EvC综合征发病机制中的作用。《基因》53:612 - 626，2015年。© 2015威利期刊公司
