PDF(Pubmed)
Abstract：
Genome-wide association studies (GWAS) have identified a large number of candidate genes believed to affect longitudinal bone growth and bone mass. One of these candidate genes, TMEM263, encodes a poorly characterized plasma membrane protein. Single nucleotide polymorphisms in TMEM263 are associated with bone mineral density in humans and mutations are associated with dwarfism in chicken and severe skeletal dysplasia in at least one human fetus. Whether this genotype-phenotype relationship is causal, however, remains unclear. Here, we determine whether and how TMEM263 is required for postnatal growth. Deletion of the Tmem263 gene in mice causes severe postnatal growth failure, proportional dwarfism, and impaired skeletal acquisition. Mice lacking Tmem263 show no differences in body weight within the first 2 weeks of postnatal life. However, by P21 there is a dramatic growth deficit due to a disrupted growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis, which is critical for longitudinal bone growth. Tmem263-null mice have low circulating IGF-1 levels and pronounced reductions in bone mass and growth plate length. The low serum IGF-1 in Tmem263-null mice is associated with reduced hepatic GH receptor (GHR) expression and GH-induced JAK2/STAT5 signaling. A deficit in GH signaling dramatically alters GH-regulated genes and feminizes the liver transcriptome of Tmem263-null male mice, with their expression profile resembling wild-type female, hypophysectomized male, and Stat5b-null male mice. Collectively, our data validates the causal role for Tmem263 in regulating postnatal growth and raises the possibility that rare mutations or variants of TMEM263 may potentially cause GH insensitivity and impair linear growth.
摘要：
全基因组关联研究（GWAS）已经确定了大量被认为影响纵向骨生长和骨量的候选基因。其中一个候选基因，TMEM263编码一种特征不佳的质膜蛋白。TMEM263中的单核苷酸多态性与人类的骨矿物质密度有关，突变与鸡的侏儒症和至少一个人类胎儿的严重骨骼发育不良有关。这种基因型-表型关系是否是因果关系，然而,尚不清楚。这里,我们确定出生后生长是否需要TMEM263以及如何需要TMEM263。小鼠中Tmem263基因的缺失会导致严重的出生后生长障碍，比例侏儒症，和骨骼获取受损。缺乏Tmem263的小鼠在出生后的前2周内没有体重差异。然而,通过P21，由于生长激素（GH）/胰岛素样生长因子1（IGF-1）轴的破坏，这对纵向骨骼生长至关重要。Tmem263-null小鼠的循环IGF-1水平较低，骨量和生长板长度明显减少。Tmem263缺失小鼠中的低血清IGF-1与肝GH受体(GHR)表达减少和GH诱导的JAK2/STAT5信号传导相关。GH信号的缺陷极大地改变了GH调节的基因，并使Tmem263-null雄性小鼠的肝脏转录组女性化，它们的表达谱类似于野生型雌性，切除垂体的男性，和Stat5b-null雄性小鼠。总的来说，我们的数据验证了Tmem263在调节出生后生长中的因果作用,并增加了TMEM263的罕见突变或变异可能导致GH不敏感和损害线性生长的可能性.
