Hypophosphatemic osteosclerosis, hyperostosis, and enthesopathy associated with novel homozygous mutations of DMP1 encoding dentin matrix protein 1 and SPP1 encoding osteopontin: The first digenic SIBLING protein osteopathy?
Hypophosphatemic osteosclerosis, hyperostosis, and enthesopathy associated with novel homozygous mutations of DMP1 encoding dentin matrix protein 1 and SPP1 encoding osteopontin: The first digenic SIBLING protein osteopathy?
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DOI：
10.1016/j.bone.2019.115190
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发表时间：
2019-12
期刊：
影响因子：
4.1
通讯作者：
M. Whyte;S. D. Amalnath;W. Mcalister;M. McKee;D. Veis;M. Huskey;Shenghui Duan;Vinieth N. Bijanki;S. Alur;S. Mumm
中科院分区：
文献类型：
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作者：
M. Whyte;S. D. Amalnath;W. Mcalister;M. McKee;D. Veis;M. Huskey;Shenghui Duan;Vinieth N. Bijanki;S. Alur;S. Mumm
SIBLING 是分泌型钙结合磷蛋白的一个亚家族，包含五个小的整合素结合配体 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) 也称为骨唾液酸蛋白 (BSP)、基质细胞外磷酸糖蛋白 (MEPE) 和牙本质唾液酸磷蛋白（DSPP）]。每个 SIBLING 至少具有一个“富含酸性、丝氨酸和天冬氨酸的基序”(ASARM) 和多个 Ser-x-Glu/pSer 序列，当磷酸化时，这些序列可促进蛋白质与羟基磷灰石的结合，从而调节生物矿化。迄今为止，由编码 SIBLING 的基因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，以及DMP1，导致常染色体隐性低磷血症性佝偻病，1型（ARHR1）。尚未报告因 DSP 或 DMP1 的功能获得突变或 SPP1、IBSP 或 MEPE 的改变引起的疾病。在此，我们描述了来自印度南部同族家庭的一名中年男子和一名年轻女子患有与骨骼畸形、身材矮小、附着病、牙齿脱落和高循环 FGF23 水平相关的严重低磷血症性骨硬化和骨质增生。两者在编码 SIBLING 蛋白的两个基因中共享新的纯合突变：停止增益（“无义”）DMP1（c.556G>T，p.Glu186Ter）和错义SPP1（c.769C>T，p.Leu266Phe）。这名男子还在另外两个基因中携带了新的杂合错义变异，这些基因调节矿物质稳态，是常染色体隐性遗传疾病的基础：CYP27B1是维生素D依赖性佝偻病1型的基础，ABCC6是婴儿期广泛动脉钙化2型和弹性假黄瘤（PXE）的基础。通过免疫化学检测，他的骨头含有大量 OPN，尤其是周围的骨细胞。我们回顾了我们患者的疾病如何代表第一个双基因 SIBLING 蛋白骨病。
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 involveDSPPcausing various autosomal dominant dysplasias of dentin but without skeletal disease, andDMP1causing autosomal recessive hypophosphatemic rickets, type 1 (ARHR1). No diseases have been reported from gain-of-function mutation(s) ofDSPPorDMP1or from alterations ofSPP1,IBSP, orMEPE.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 missenseSPP1(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:CYP27B1underlying vitamin D dependent rickets, type 1, andABCC6underlying 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.