Otto Florian, Kanegane Hirokazu, Mundlos Stefan
Department of Hematology/Oncology, University of Freiburg Medical Center, Freiburg, Germany.
Hum Mutat. 2002 Mar;19(3):209-16. doi: 10.1002/humu.10043.
Cleidocranial dysplasia (CCD) is a autosomal dominant disorder characterized by skeletal anomalies such as patent fontanels, late closure of cranial sutures with Wormian bones, late erupting secondary dentition, rudimentary clavicles, and short stature. The locus for this disease was mapped to chromosome 6p21. RUNX2 is a member of the runt family of transcription factors and its expression is restricted to developing osteoblasts and a subset of chondrocytes. Mutations in the RUNX2 gene have been shown to cause CCD. Chromosomal translocations, deletions, insertions, nonsense and splice-site mutations, as well as missense mutations of the RUNX2 gene have been described in CCD patients. Although there is a wide spectrum in phenotypic variability ranging from primary dental anomalies to all CCD features plus osteoporosis, no clear phenotype-genotype correlation has been established. However analysis of the three-dimensional structure of the DNA binding runt domain of the RUNX proteins and its interaction with DNA, as well as the cofactor CBFB, start to provide an insight into how missense mutations affect RUNX2 function.
锁骨颅骨发育不全（CCD）是一种常染色体显性疾病，其特征为骨骼异常，如囟门未闭、颅缝闭合延迟并伴有缝间骨、恒牙萌出延迟、锁骨发育不全和身材矮小。该疾病的基因座定位于6号染色体p21。RUNX2是转录因子 runt 家族的成员，其表达仅限于发育中的成骨细胞和一部分软骨细胞。已证明RUNX2基因突变会导致CCD。在CCD患者中已发现RUNX2基因的染色体易位、缺失、插入、无义突变和剪接位点突变，以及错义突变。尽管从原发性牙齿异常到所有CCD特征加骨质疏松症，其表型变异范围很广，但尚未建立明确的表型-基因型相关性。然而，对RUNX蛋白的DNA结合runt结构域的三维结构及其与DNA以及辅因子CBFB的相互作用进行分析，开始为错义突变如何影响RUNX2功能提供了见解。
