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母细胞蛋白的功能提供了有价值的见解。然而，除了与遗传性疾病有关的错义和功能缺失外，它们在人类中的功能仍不清楚。基因组聚合数据库中来自140,000多个个体的深层外显子组测序数据的可用性提供了一个机会，可以检查对人类基质细胞基因功能丧失和错义突变的不耐受性。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）以及分泌的蛋白，酸性蛋白和酸性蛋白的成员之间，功能丧失不耐受（pLI）的可能性差异很大。富含半胱氨酸（SPARC）基因家族。值得注意的是 人类的pLI值与相应的纯合无效小鼠的生存力之间的关联有限。在血小板反应蛋白中，只有THBS1具有高度的抗损失能力（pLI = 1）。相反，Thbs1对于小鼠的生存力不是必需的。几种已知的血小板反应蛋白1受体具有类似的抗丢失能力，尽管血小板反应蛋白1不是其中某些受体的排他性配体。THBS1中的错义突变的频率和编码其信号受体CD47的基因表明某些与特定受体结合有关的残基保守。其他血小板反应蛋白基因和SPARC，SPOCK1，SPOCK2，TNR和DSPP的错义突变也存在缺陷。THBS1的不耐受人类功能丧失和THBS2，SPARC，SPOCK1，TNR和CCN1的pLI值升高支持人类这些基质细胞蛋白基因的重要功能，其中一些可能与生殖功能或对环境压力的响应有关。