Loss-of-function mutations in LEMD3 result in osteopoikilosis, Buschke-Ollendorff syndrome and melorheostosis
Loss-of-function mutations in LEMD3 result in osteopoikilosis, Buschke-Ollendorff syndrome and melorheostosis
复制标题
DOI：
10.1038/ng1453
复制
发表时间：
2004-11-01
期刊：
影响因子：
30.8
通讯作者：
Mortier, GR
中科院分区：
文献类型：
--
作者：
Hellemans, J;Preobrazhenska, O;Mortier, GR
骨质疏松症、Buschke-Ollendorff综合征（BOS）和骨质疏松症都是以骨密度增高为特征的疾病(1)。在同一个体或家族中出现一种或多种这些表型表明这些实体可能是等位的（2-4）。我们收集了来自三个家庭的数据，这些家庭中受影响的个体有骨质疏松症，有或没有BOS或骨质疏松症的表现。在这些家庭中进行全基因组连锁分析，然后在患有这些疾病的不相关个体中鉴定微缺失，使我们能够绘制出在骨质疏松症中突变的基因。我们调查的所有受影响的个体在编码核膜蛋白的LEMD3（也称为MAN1）的功能丧失突变方面都是杂合的。在BOS患者和黑色素瘤患者受影响皮肤的成纤维细胞中，无法鉴定出LEMD3第二个等位基因的体细胞突变。Xenopus laevis同源基因XMAN1在胚胎发生过程中拮抗BMP信号传导(5)。在这项研究中，LEMD3与BMP和激活素- tgfp受体激活的Smads相互作用，并在人类细胞中拮抗这两种信号通路。
Osteopoikilosis, Buschke-Ollendorff syndrome (BOS) and melorheostosis are disorders characterized by increased bone density(1). The occurrence of one or more of these phenotypes in the same individual or family suggests that these entities might be allelic(2-4). We collected data from three families in which affected individuals had osteopoikilosis with or without manifestations of BOS or melorheostosis. A genome-wide linkage analysis in these families, followed by the identification of a microdeletion in an unrelated individual with these diseases, allowed us to map the gene that is mutated in osteopoikilosis. All the affected individuals that we investigated were heterozygous with respect to a loss-of-function mutation in LEMD3 (also called MAN1), which encodes an inner nuclear membrane protein. A somatic mutation in the second allele of LEMD3 could not be identified in fibroblasts from affected skin of an individual with BOS and an individual with melorheostosis. XMAN1, the Xenopus laevis ortholog, antagonizes BMP signaling during embryogenesis(5). In this study, LEMD3 interacted with BMP and activin-TGFP receptor-activated Smads and antagonized both signaling pathways in human cells.