Center for Metabolic Bone Disease and Molecular Research, Shriners Hospitals for Children - St. Louis, St. Louis, MO 63110, USA; Division of Bone and Mineral Diseases, Department of Internal Medicine, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, MO 63110, USA.
Department of Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research, Pondicherry 605006, India.
Bone. 2020 Mar;132:115190. doi: 10.1016/j.bone.2019.115190. Epub 2019 Dec 13.
The SIBLINGs are a subfamily of the secreted calcium-binding phosphoproteins and comprise five small integrin-binding ligand N-linked glycoproteins [dentin matrix protein-1 (DMP1), secreted phosphoprotein-1 (SPP1) also called osteopontin (OPN), integrin-binding sialoprotein (IBSP) also called bone sialoprotein (BSP), matrix extracellular phosphoglycoprotein (MEPE), and dentin sialophosphoprotein (DSPP)]. Each SIBLING has at least one "acidic, serine- and aspartic acid-rich motif" (ASARM) and multiple Ser-x-Glu/pSer sequences that when phosphorylated promote binding of the protein to hydroxyapatite for regulation of biomineralization. Mendelian disorders from loss-of-function mutation(s) of the genes that encode the SIBLINGs thus far involve DSPP causing various autosomal dominant dysplasias of dentin but without skeletal disease, and DMP1 causing autosomal recessive hypophosphatemic rickets, type 1 (ARHR1). No diseases have been reported from gain-of-function mutation(s) of DSPP or DMP1 or from alterations of SPP1, IBSP, or MEPE. Herein, we describe severe hypophosphatemic osteosclerosis and hyperostosis associated with skeletal deformity, short stature, enthesopathy, tooth loss, and high circulating FGF23 levels in a middle-aged man and young woman from an endogamous family living in southern India. Both shared novel homozygous mutations within two genes that encode a SIBLING protein: stop-gain ("nonsense") DMP1 (c.556G>T,p.Glu186Ter) and missense SPP1 (c.769C>T,p.Leu266Phe). The man alone also carried novel heterozygous missense variants within two additional genes that condition mineral homeostasis and are the basis for autosomal recessive disorders: CYP27B1 underlying vitamin D dependent rickets, type 1, and ABCC6 underlying both generalized arterial calcification of infancy, type 2 and pseudoxanthoma elasticum (PXE). By immunochemistry, his bone contained high amounts of OPN, particularly striking surrounding osteocytes. We review how our patients' disorder may represent the first digenic SIBLING protein osteopathy.
SIBLINGs 是分泌型钙结合磷酸化蛋白的一个亚家族，包含五个小整合素结合配体 N 连接糖蛋白 [牙本质基质蛋白-1（DMP1）、分泌型磷蛋白-1（SPP1）也称为骨桥蛋白（OPN）、整合素结合唾液酸蛋白（IBSP）也称为骨唾液蛋白（BSP）、基质细胞外磷糖蛋白（MEPE）和牙本质涎磷蛋白（DSPP）]。每个 SIBLING 至少有一个“酸性、丝氨酸和天冬氨酸丰富的基序”（ASARM）和多个 Ser-x-Glu/pSer 序列，当磷酸化时，促进蛋白质与羟基磷灰石结合，以调节生物矿化。迄今为止，由于编码 SIBLING 的基因发生功能丧失突变引起的孟德尔疾病涉及 DSPP，导致各种常染色体显性牙本质发育不良，但没有骨骼疾病，而 DMP1 导致常染色体隐性低磷血症性佝偻病，1 型（ARHR1）。尚未报道 DSPP 或 DMP1 的功能获得性突变或 SPP1、IBSP 或 MEPE 的改变引起的疾病。在此，我们描述了一名中年男子和一名年轻女子的严重低磷血症性骨硬化症和骨肥厚，伴有骨骼畸形、身材矮小、腱病、牙齿缺失和循环中高 FGF23 水平，他们来自生活在印度南部的一个近亲通婚家庭。两人均在编码 SIBLING 蛋白的两个基因中共享新的纯合突变：无义突变（“无义”）DMP1（c.556G>T，p.Glu186Ter）和错义 SPP1（c.769C>T，p.Leu266Phe）。该男子还单独携带两个调节矿物质稳态的额外基因的新杂合错义变体，这些基因是常染色体隐性疾病的基础：CYP27B1 引起维生素 D 依赖性佝偻病，1 型和 ABCC6 引起婴儿全身性动脉钙化，2 型和假性黄色瘤弹性组织营养不良（PXE）。通过免疫化学，他的骨组织中含有大量的 OPN，特别是围绕着骨细胞的 OPN 尤为明显。我们回顾了患者的疾病可能代表首个双基因 SIBLING 蛋白骨病。
