Guerrini Matteo M, Sobacchi Cristina, Cassani Barbara, Abinun Mario, Kilic Sara S, Pangrazio Alessandra, Moratto Daniele, Mazzolari Evelina, Clayton-Smith Jill, Orchard Paul, Coxon Fraser P, Helfrich Miep H, Crockett Julie C, Mellis David, Vellodi Ashok, Tezcan Ilhan, Notarangelo Luigi D, Rogers Michael J, Vezzoni Paolo, Villa Anna, Frattini Annalisa
Istituto di Tecnologie Biomediche, Consiglio Nazionale delle Ricerche, Segrate 20090, Italy.
Am J Hum Genet. 2008 Jul;83(1):64-76. doi: 10.1016/j.ajhg.2008.06.015.
Autosomal-Recessive Osteopetrosis (ARO) comprises a heterogeneous group of bone diseases for which mutations in five genes are known as causative. Most ARO are classified as osteoclast-rich, but recently a subset of osteoclast-poor ARO has been recognized as due to a defect in TNFSF11 (also called RANKL or TRANCE, coding for the RANKL protein), a master gene driving osteoclast differentiation along the RANKL-RANK axis. RANKL and RANK (coded for by the TNFRSF11A gene) also play a role in the immune system, which raises the possibility that defects in this pathway might cause osteopetrosis with immunodeficiency. From a large series of ARO patients we selected a Turkish consanguineous family with two siblings affected by ARO and hypogammaglobulinemia with no defects in known osteopetrosis genes. Sequencing of genes involved in the RANKL downstream pathway identified a homozygous mutation in the TNFRSF11A gene in both siblings. Their monocytes failed to differentiate in vitro into osteoclasts upon exposure to M-CSF and RANKL, in keeping with an osteoclast-intrinsic defect. Immunological analysis showed that their hypogammaglobulinemia was associated with impairment in immunoglobulin-secreting B cells. Investigation of other patients revealed a defect in both TNFRSF11A alleles in six additional, unrelated families. Our results indicate that TNFRSF11A mutations can cause a clinical condition in which severe ARO is associated with an immunoglobulin-production defect.
常染色体隐性遗传性骨质石化症（ARO）是一组异质性骨病，已知五个基因的突变是其病因。大多数ARO被归类为富含破骨细胞型，但最近已认识到一部分破骨细胞缺乏型ARO是由于TNFSF11（也称为RANKL或TRANCE，编码RANKL蛋白）缺陷所致，TNFSF11是驱动破骨细胞沿RANKL-RANK轴分化的主基因。RANKL和RANK（由TNFRSF11A基因编码）在免疫系统中也发挥作用，这增加了该信号通路缺陷可能导致伴有免疫缺陷的骨质石化症的可能性。从一大组ARO患者中，我们选择了一个土耳其近亲家庭，该家庭中有两名受ARO和低丙种球蛋白血症影响的兄弟姐妹，且已知的骨质石化症基因无缺陷。对RANKL下游信号通路相关基因进行测序，发现两名兄弟姐妹的TNFRSF11A基因均存在纯合突变。他们的单核细胞在体外暴露于M-CSF和RANKL后未能分化为破骨细胞，这与破骨细胞内在缺陷一致。免疫分析表明，他们的低丙种球蛋白血症与分泌免疫球蛋白的B细胞功能受损有关。对其他患者的调查显示，另外六个不相关家庭的TNFRSF11A等位基因均存在缺陷。我们的结果表明，TNFRSF11A突变可导致一种临床病症，即严重ARO与免疫球蛋白产生缺陷相关。
