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A Novel Splice Muta...
A Novel Splice Mutation in PLS3 Causes X-linked Early Onset Low-Turnover Osteoporosis
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- Laine, Christine M. (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för medicin,Institute of Medicine
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Wessman, M. (författare)
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Toiviainen-Salo, S. (författare)
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Kaunisto, M. A. (författare)
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Mayranpaa, M. K. (författare)
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- Laine, Tero (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för ortopedi,Institute of Clinical Sciences, Department of Orthopaedics
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Pekkinen, M. (författare)
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Kroger, H. (författare)
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Valimaki, V. V. (författare)
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Valimaki, M. J. (författare)
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Lehesjoki, A. E. (författare)
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- Makitie, O. (författare)
- Karolinska Institutet
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(creator_code:org_t)
- 2015-02-16
- 2015
- Engelska.
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Ingår i: Journal of Bone and Mineral Research. - : Wiley. - 0884-0431. ; 30:3, s. 437-445
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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(not asymptotic to)17). The mutation affects the first N-terminal calcium-binding EF-hand domain and abolishes all calcium-and actinbinding 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. (C) 2014 American Society for Bone and Mineral Research.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)
Nyckelord
- OSTEOPOROSIS
- BONE HISTOMORPHOMETRY
- GENETIC RESEARCH
- CELLS OF BONE
- BIOCHEMICAL MARKERS OF BONE TURNOVER
- OSTEOGENESIS IMPERFECTA
- BONE HISTOMORPHOMETRY
- CHILDHOOD FRACTURES
- GENETIC-VARIANTS
- PROTEINS
- CHILDREN
- BINDING
- PLASTIN
- GAIN
- Endocrinology & Metabolism
- NANT HK
- 1993
- JOURNAL OF BONE AND MINERAL RESEARCH
- V8
- P1137
- ARRUDA MV
- 1990
- JOURNAL OF CELL BIOLOGY
- V111
- P1069
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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Till lärosätets databas
- Av författaren/redakt...
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Laine, Christine ...
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Wessman, M.
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Toiviainen-Salo, ...
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Kaunisto, M. A.
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Mayranpaa, M. K.
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Laine, Tero
-
visa fler...
-
Pekkinen, M.
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Kroger, H.
-
Valimaki, V. V.
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Valimaki, M. J.
-
Lehesjoki, A. E.
-
Makitie, O.
-
visa färre...
- Om ämnet
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Klinisk medicin
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och Endokrinologi oc ...
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Journal of Bone ...
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Journal of bone ...
- Av lärosätet
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Göteborgs universitet
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Karolinska Institutet