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?
| Autor: | Michael P. Whyte, Vinieth N. Bijanki, Deborah J. Veis, Shenghui Duan, Margaret Huskey, William H. McAlister, Suhas Alur, S. Deepak Amalnath, Marc D. McKee, Steven Mumm |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Bone sialoprotein Histology Physiology Endocrinology Diabetes and Metabolism India 030209 endocrinology & metabolism Enthesopathy Biology Article 03 medical and health sciences Osteosclerosis 0302 clinical medicine stomatognathic system Dentin sialophosphoprotein medicine Humans Missense mutation Osteopontin Genetics Extracellular Matrix Proteins Hyperostosis Middle Aged Phosphoproteins Pseudoxanthoma elasticum medicine.disease DMP1 3. Good health Fibroblast Growth Factor-23 030104 developmental biology Dentin Mutation MEPE biology.protein Female |
| Zdroj: | Bone |
| ISSN: | 8756-3282 |
| Popis: | 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 (BPS), 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 (“non-sense”) 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. |
| Databáze: | OpenAIRE |
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