Long-Term Clinical Outcome and Carrier Phenotype in Autosomal Recessive Hypophosphatemia Caused by a Novel DMP1 Mutation
| Autor: | Heikki Kröger, Outi Mäkitie, William G. Cole, Renata C. Pereira, Tero Laine, Serap Turan, Murat Bastepe, Harald Jüppner, Ilkka Kaitila |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Fibroblast growth factor 23
Male medicine.medical_specialty DMP1 Endocrinology Diabetes and Metabolism 030209 endocrinology & metabolism Genes Recessive osteomalacia skeletal dysplasia Bone remodeling 03 medical and health sciences 0302 clinical medicine stomatognathic system Internal medicine rickets Medicine Humans Orthopedics and Sports Medicine Bone pain 030304 developmental biology Aged hypophosphatemia 0303 health sciences Osteomalacia FGF-23 Extracellular Matrix Proteins business.industry Genetic Carrier Screening Heterozygote advantage medicine.disease Phosphoproteins Pedigree Hypophosphatemic Rickets Fibroblast Growth Factor-23 Endocrinology Phenotype Mutation Original Article Female medicine.symptom business Hypophosphatemia |
| Zdroj: | Journal of Bone and Mineral Research |
| ISSN: | 1523-4681 0884-0431 |
| Popis: | Homozygous inactivating mutations in DMP1 (dentin matrix protein 1), the gene encoding a noncollagenous bone matrix protein expressed in osteoblasts and osteocytes, cause autosomal recessive hypophosphatemia (ARHP). Herein we describe a family with ARHP owing to a novel homozygous DMP1 mutation and provide a detailed description of the associated skeletal dysplasia and carrier phenotype. The two adult patients with ARHP, a 78-year-old man and his 66-year-old sister, have suffered from bone pain and lower extremity varus deformities since early childhood. With increasing age, both patients developed severe joint pain, contractures, and complete immobilization of the spine. Radiographs showed short and deformed long bones, significant cranial hyperostosis, enthesopathies, and calcifications of the paraspinal ligaments. Biochemistries were consistent with hypophosphatemia owing to renal phosphate wasting; markers of bone turnover and serum fibroblast growth factor 23 (FGF-23) levels were increased significantly. Nucleotide sequence analysis of DMP1 revealed a novel homozygous mutation at the splice acceptor junction of exon 6 (IVS5-1G > A). Two heterozygous carriers of the mutation also showed mild hypophosphatemia, and bone biopsy in one of these individuals showed focal areas of osteomalacia. In bone, DMP1 expression was absent in the homozygote but normal in the heterozygote, whereas FGF-23 expression was increased in both subjects but higher in the ARHP patient. The clinical and laboratory observations in this family confirm that DMP1 has an important role in normal skeletal development and mineral homeostasis. The skeletal phenotype in ARHP may be significantly more severe than in other forms of hypophosphatemic rickets. © 2010 American Society for Bone and Mineral Research. |
| Databáze: | OpenAIRE |
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