Zhang Y W, Yasui N, Kakazu N, Abe T, Takada K, Imai S, Sato M, Nomura S, Ochi T, Okuzumi S, Nogami H, Nagai T, Ohashi H, Ito Y
Department of Viral Oncology, Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto, Japan.
Gene. 2000 Feb 22;244(1-2):21-8. doi: 10.1016/s0378-1119(99)00558-2.
Cleidocranial dysplasia (CCD) is an autosomal dominant human bone disease whose genetic locus has been located on chromosome 6p21, where the PEBP2alphaA/CBFA1 gene essential for osteogenesis also maps. Previously, several heterozygous mutations in PEBP2alphaA/CBFA1 were found in CCD patients. In this study, we identified six different types of mutations in PEBP2alphaA/CBFA1 in Japanese CCD patients. Four cases were similar to those reported previously: two were nonsense mutations in the Runt domain, one was a hemizygous deletion, and the other was a missense mutation in the Runt domain which abolished the DNA-binding activity of Runx2/PEBP2alphaA/CBFA1. The remaining two mutations were novel: one had a heterozygous gt-to-tt mutation at the splice donor site (gt) between the exon3-intron junction, which resulted in abnormal exon3 skipping, and the other had a mutation in exon7, which led to the introduction of a translational stop codon in the middle of the transactivation domain. Thus, defects in either the DNA-binding domain or transactivation domain of Runx2/PEBP2alphaA/CBFA1 can cause CCD. The results not only provide a strong genetic evidence that mutations involving in PEBP2alphaA/CBFA1 contribute to CCD, but also provide a useful tool to study how Runx2/PEBP2alphaA/CBFA1 plays its pivotal role during osteoblastic differentiation.
锁骨颅骨发育不全（CCD）是一种常染色体显性遗传的人类骨骼疾病，其基因位点位于6号染色体短臂21区，而成骨所必需的PEBP2αA/CBFA1基因也定位于此区域。此前，在CCD患者中发现了PEBP2αA/CBFA1的几种杂合突变。在本研究中，我们在日本CCD患者中鉴定出了PEBP2αA/CBFA1的六种不同类型突变。其中四例与先前报道的相似：两例为Runt结构域的无义突变，一例为半合子缺失，另一例为Runt结构域的错义突变，该突变消除了Runx2/PEBP2αA/CBFA1的DNA结合活性。其余两种突变是新发现的：一种在外显子3-内含子交界处的剪接供体位点（gt）存在杂合的gt-to-tt突变，导致外显子3异常跳跃；另一种在外显子七中有突变，导致在反式激活结构域中部引入了一个翻译终止密码子。因此，Runx2/PEBP2αA/CBFA1的DNA结合结构域或反式激活结构域的缺陷均可导致CCD。这些结果不仅为涉及PEBP2αA/CBFA1的突变导致CCD提供了有力的遗传学证据，也为研究Runx2/PEBP2αA/CBFA1在成骨细胞分化过程中如何发挥关键作用提供了有用的工具。
