CBFA1 mutation analysis and functional correlation with phenotypic variability in cleidocranial dysplasia
CBFA1 mutation analysis and functional correlation with phenotypic variability in cleidocranial dysplasia
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DOI：
10.1093/hmg/8.12.2311
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发表时间：
1999-11-01
影响因子：
3.5
通讯作者：
Lee, B
中科院分区：
文献类型：
--
作者：
Zhou, G;Chen, YQ;Lee, B
锁骨颅骨发育不良（Cleidocranial dysplasia，CCD）是一种由成骨细胞特异性转录因子CBFA 1突变引起的显性遗传性骨骼发育不良。为了将CBFA 1不同功能域的突变与CCD的临床表现联系起来，我们研究了26例独立的CCD病例，在17个家系中共发现了16个新的突变，大多数突变是从头错义突变，其影响runt结构域中的保守残基并完全消除DNA结合和报告基因的反式激活。和突变，导致在runt结构域的提前终止，产生了一个典型的CCD表型，通过消除反式激活的突变蛋白，随之而来的单倍不足，我们进一步确定了三个假定的亚型突变（R391X、T200A和90insC），其导致包括典型和轻度CCD的临床谱，以及以恒牙延迟萌出为特征的孤立的牙齿表型，功能研究表明，三个突变中的两个是亚型的，两个与显著的家族内可变表达相关，这些数据共同表明，由于CBFA 1的runt和PST结构域的改变而引起的可变功能丧失可能引起临床变异，包括经典CCD、轻度CCD和孤立的原发性牙齿异常。
Cleidocranial dysplasia (CCD) is a dominantly inherited skeletal dysplasia caused by mutations in the osteoblast-specific transcription factor CBFA1, To correlate CBFA1 mutations in different functional domains with the CCD clinical spectrum, we studied 26 independent cases of CCD and a total of 16 new mutations were identified in 17 families, The majority of mutations were de novo missense mutations that affected conserved residues in the runt domain and completely abolished both DNA binding and transactivation of a reporter gene, These, and mutations which result in premature termination in the runt domain, produced a classic CCD phenotype by abolishing transactivation of the mutant protein with consequent haploinsufficiency, We further identified three putative hypomorphic mutations (R391X, T200A and 90insC) which result in a clinical spectrum including classic and mild CCD, as well as an isolated dental phenotype characterized by delayed eruption of permanent teeth, Functional studies show that two of the three mutations were hypomorphic in nature and two were associated with significant intrafamilial variable expressivity, including isolated dental anomalies without the skeletal features of CCD, Together these data show that variable loss of function due to alterations in the runt and PST domains of CBFA1 may give rise to clinical variability, including classic CCD, mild CCD and isolated primary dental anomalies.