Kaur Sukhbir, Roberts David D
Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Building 10 Room 2S235, 10 Center Drive MSC1500, Bethesda, MD, 20892-1500, USA.
J Cell Commun Signal. 2021 Mar;15(1):93-105. doi: 10.1007/s12079-020-00598-9. Epub 2021 Jan 7.
Targeted gene disruption in mice has provided valuable insights into the functions of matricellular proteins. Apart from missense and loss of function mutations that have been associated with inherited diseases, however, their functions in humans remain unclear. The availability of deep exome sequencing data from over 140,000 individuals in the Genome Aggregation Database provided an opportunity to examine intolerance to loss of function and missense mutations in human matricellular genes. The probability of loss-of-function intolerance (pLI) differed widely within members of the thrombospondin, CYR61/CTGF/NOV (CCN), tenascin, small integrin-binding ligand N-linked glycoproteins (SIBLING), and secreted protein, acidic and rich in cysteine (SPARC) gene families. Notably, pLI values in humans had limited correlation with viability of the corresponding homozygous null mice. Among the thrombospondins, only THBS1 was highly loss-intolerant (pLI = 1). In contrast, Thbs1 is not essential for viability in mice. Several known thrombospondin-1 receptors were similarly loss-intolerant, although thrombospondin-1 is not the exclusive ligand for some of these receptors. The frequencies of missense mutations in THBS1 and the gene encoding its signaling receptor CD47 indicated conservation of some residues implicated in specific receptor binding. Deficits in missense mutations were also observed for other thrombospondin genes and for SPARC, SPOCK1, SPOCK2, TNR, and DSPP. The intolerance of THBS1 to loss of function in humans and elevated pLI values for THBS2, SPARC, SPOCK1, TNR, and CCN1 support important functions for these matricellular protein genes in humans, some of which may relate to functions in reproduction or responding to environmental stresses.
小鼠中的靶向基因破坏为深入了解基质细胞蛋白的功能提供了有价值的见解。然而，除了与遗传性疾病相关的错义突变和功能丧失突变外，它们在人类中的功能仍不清楚。基因组聚合数据库中超过140,000人的深度外显子测序数据，为研究人类基质细胞基因功能丧失和错义突变的不耐受性提供了契机。血小板反应蛋白、CYR61/CTGF/NOV（CCN）、腱生蛋白、小整合素结合配体N-连接糖蛋白（SIBLING）和富含半胱氨酸的酸性分泌蛋白（SPARC）基因家族成员之间，功能丧失不耐受概率（pLI）差异很大。值得注意的是，人类的pLI值与相应纯合敲除小鼠的生存能力相关性有限。在血小板反应蛋白中，只有THBS1高度不耐功能丧失（pLI = 1）。相比之下，Thbs1对小鼠的生存并非必需。几种已知的血小板反应蛋白-1受体同样不耐功能丧失，尽管血小板反应蛋白-1并非其中某些受体的唯一配体。THBS1及其信号受体CD47编码基因中的错义突变频率表明，一些与特定受体结合有关的残基具有保守性。在其他血小板反应蛋白基因以及SPARC、SPOCK1、SPOCK2、TNR和DSPP中也观察到错义突变缺陷。THBS1在人类中对功能丧失的不耐受性以及THBS2、SPARC、SPOCK1、TNR和CCN1升高的pLI值，支持了这些基质细胞蛋白基因在人类中的重要功能，其中一些可能与生殖功能或对环境应激的反应有关。
