Mutations in the human Delta homologue, DLL3, cause axial skeletal defects in spondylocostal dysostosis
Mutations in the human Delta homologue, DLL3, cause axial skeletal defects in spondylocostal dysostosis
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DOI：
10.1038/74307
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发表时间：
2000-04-01
期刊：
影响因子：
30.8
通讯作者：
Turnpenny, PD
中科院分区：
文献类型：
--
作者：
Bulman, MP;Kusumi, K;Turnpenny, PD
脊椎肋骨发育不全（SD，MIM 277300）是一组椎体分割不良综合征，由于轴向骨骼缺陷导致身高降低。SD的特征是多个半椎体、肋骨融合和缺失，伴有非进行性脊柱后凸。病例可能是散发性或家族性的，常染色体显性和常染色体隐性遗传方式均有报道[1]。常染色体隐性SD定位于染色体19q13.1-q13.3上的7.8cM区间（参考文献，2），该区间与含有编码Notch配体δ样3（DII 3）的基因的小鼠区域同源。DII 3在X射线诱导的小鼠突变体pudgy（pu）中发生突变（3），导致与SD表型相似的各种脊椎肋骨缺陷。在这里，我们已经克隆和测序人类DLL 3评估它作为一个候选基因的SD和确定的突变在三个常染色体隐性SD家庭。其中两个突变预测保守的细胞外结构域内的截短。第三个是第五表皮生长因子（EGF）重复序列的一个高度保守的甘氨酸残基中的错义突变，这揭示了该结构域的重要功能作用。这些代表了人类Delta同源物中的第一个突变，从而突出了Notch信号通路及其组分在哺乳动物中轴骨骼模式中的关键作用。
Spondylocostal dysostosis (SD, MIM 277300) is a group of vertebral malsegmentation syndromes with reduced stature resulting from axial skeletal defects. SD is characterized by mu[tiple hemivertebrae, rib fusions and deletions with a non-progressive kyphoscoliosis. Cases may be sporadic or familial, with both autosomal dominant and autosomal recessive modes of inheritance reported(1). Autosomal recessive SD maps to a 7.8cM interval on chromosome 19q13.1-q13.3 (ref, 2) that is homologous with a mouse region containing a gene encoding the Notch ligand delta-like 3 (DII3). DII3 is mutated(3) in the Xray-induced mouse mutant pudgy (pu), causing a variety of vertebrocostal defects similar to SD phenotypes. Here we have cloned and sequenced human DLL3 to evaluate it as a candidate gene for SD and identified mutations in three autosomal recessive SD families. Two of the mutations predict truncations within conserved extracellular domains. The third is a missense mutation in a highly conserved glycine residue of the fifth epidermal growth factor (EGF) repeat, which has revealed an important functional role for this domain. These represent the first mutations in a human Delta homologue, thus highlighting the critical role of the Notch signalling pathway and its components in patterning the mammalian axial skeleton.