A Novel Splice Mutation inPLS3Causes X-linked Early Onset Low-Turnover Osteoporosis
| Autor: | Heikki Kröger, Sanna Toiviainen-Salo, Minna Pekkinen, Outi Mäkitie, Maija Wessman, Mervi K Mäyränpää, Anna-Elina Lehesjoki, Matti Välimäki, Ville-Valtteri Välimäki, Christine M. Laine, Mari A. Kaunisto, Tero Laine |
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| Rok vydání: | 2015 |
| Předmět: |
Bone mineral
0303 health sciences medicine.medical_specialty Mutation Osteoid Endocrinology Diabetes and Metabolism Osteoporosis 030209 endocrinology & metabolism Biology medicine.disease medicine.disease_cause Frameshift mutation 03 medical and health sciences 0302 clinical medicine Endocrinology medicine.anatomical_structure Osteogenesis imperfecta Internal medicine Osteocyte medicine PLS3 Orthopedics and Sports Medicine 030304 developmental biology |
| Zdroj: | Journal of Bone and Mineral Research. 30:510-518 |
| ISSN: | 0884-0431 |
| DOI: | 10.1002/jbmr.2355 |
| Popis: | Genetic factors play an important role in the development of osteoporosis. Several monogenic forms of osteoporosis have been recognized, most recently an X-chromosomal form resulting from mutations in the gene encoding plastin 3 (PLS3). PLS3 is a protein involved in actin bundle formation in the cytoskeleton. We present a large family with early onset osteoporosis and X-linked inheritance. Phenotyping was performed on 19 family members and whole-exome sequencing on 7 family members (5 with a diagnosis of early onset osteoporosis and 2 with normal bone parameters). Osteoporosis had its onset in childhood and was characterized by recurrent peripheral fractures, low bone mineral density (BMD), vertebral compression fractures, and significant height loss in adulthood. Males were in general more severely affected than females. Bone histomorphometry findings in 4 males and 1 female showed severe trabecular osteoporosis, low amount of osteoid, and decreased mineral apposition rate, indicating impaired bone formation; resorption parameters were increased in some. All affected subjects shared a single base substitution (c.73-24T > A) in intron 2 of PLS3 on Xq23. The mutation, confirmed by Sanger sequencing, segregated according to the skeletal phenotype. The mutation introduces a new acceptor splice site with a predicted splice score of 0.99 and, thereby, as confirmed by cDNA sequencing, induces the insertion of 22 bases between exons 2 and 3, causing a frameshift and premature termination of mRNA translation (p.Asp25Alafs*17). The mutation affects the first N-terminal calcium-binding EF-hand domain and abolishes all calcium- and actin-binding domains of the protein. Our results confirm the role of PLS3 mutations in early onset osteoporosis. The mechanism whereby PLS3 affects bone health is unclear, but it may be linked to osteocyte dendrite function and skeletal mechanosensing. Future studies are needed to elucidate the role of PLS3 in osteoporosis and to define optimal treatment. © 2014 American Society for Bone and Mineral Research. |
| Databáze: | OpenAIRE |
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