Mutations of the GNAS1 gene, stromal cell dysfunction, and osteomalacic changes in non-McCune-Albright fibrous dysplasia of bone

P. Bianco, M. Riminucci, A. Majolagbe, S. A. Kuznetsov, M. T. Collins, M. H. Mankani, A. Corsi, H. G. Bone, S. Wientroub, Allen M. Spiegel, L. W. Fisher, Pamela Gehron Robey

Research output: Contribution to journalArticle

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Abstract

Activating missense mutations of the GNAS1 gene, encoding the α subunit of the stimulatory G protein (Gs), have been identified in patients with the McCune-Albright syndrome (MAS; characterized by polyostotic fibrous dysplasia, cafe au lait skin pigmentation, and endocrine disorders). Because fibrous dysplasia (FD) of bone also commonly occurs outside of the context of typical MAS, we asked whether the same mutations could be identified routinely in non-MAS FD lesions. We analyzed a series of 8 randomly obtained, consecutive cases of non-MAS FD and identified R201 mutations in the GNAS1 gene in all of them by sequencing cDNA generated by amplification of genomic DNA using a standard primer set and by using a novel, highly sensitive method that uses a protein nucleic acid (PNA) primer to block amplification of the normal allele. Histologic findings were not distinguishable from those observed in MAS-related FD and included subtle changes in cell shape and collagen texture putatively ascribed to excess endogenous cyclic adenosine monophosphate (cAMP). Osteomalacic changes (unmineralized osteoid) were prominent in lesional FD bone. In an in vivo transplantation assay, stromal cells isolated from FD failed to recapitulate a normal ossicle; instead, they generated a miniature replica of fibrous dysplasia. These data provide evidence that occurrence of GNAS1 mutations, previously noted in individual cases of FD, is a common and perhaps constant finding in non-MAS FD. These findings support the view that FD, MAS, and nonskeletal isolated endocrine lesions associated with GNAS1 mutations represent a spectrum of phenotypic expressions (likely reflecting different patterns of somatic mosaicism) of the same basic disorder. We conclude that mechanisms underlying the development of the FD lesions, and hopefully mechanism-targeted therapeutic approaches to be developed, must also be the same in MAS and non-MAS FD.

Original languageEnglish (US)
Pages (from-to)120-128
Number of pages9
JournalJournal of Bone and Mineral Research
Volume15
Issue number1
StatePublished - 2000
Externally publishedYes

Fingerprint

Fibrous Dysplasia of Bone
Stromal Cells
Polyostotic Fibrous Dysplasia
Mutation
Genes
Pigmentation Disorders
Gs GTP-Binding Protein alpha Subunits
Skin Pigmentation
Mosaicism
Cell Shape
Missense Mutation
Cyclic AMP
Nucleic Acids
Collagen
Complementary DNA
Transplantation
Alleles
DNA
Proteins

Keywords

  • Animal model
  • Fibrous dysplasia
  • GNAS1
  • Gsα
  • McCune-Albright syndrome
  • Mutation analysis
  • PNA
  • Transplantation

ASJC Scopus subject areas

  • Surgery

Cite this

Bianco, P., Riminucci, M., Majolagbe, A., Kuznetsov, S. A., Collins, M. T., Mankani, M. H., ... Gehron Robey, P. (2000). Mutations of the GNAS1 gene, stromal cell dysfunction, and osteomalacic changes in non-McCune-Albright fibrous dysplasia of bone. Journal of Bone and Mineral Research, 15(1), 120-128.

Mutations of the GNAS1 gene, stromal cell dysfunction, and osteomalacic changes in non-McCune-Albright fibrous dysplasia of bone. / Bianco, P.; Riminucci, M.; Majolagbe, A.; Kuznetsov, S. A.; Collins, M. T.; Mankani, M. H.; Corsi, A.; Bone, H. G.; Wientroub, S.; Spiegel, Allen M.; Fisher, L. W.; Gehron Robey, Pamela.

In: Journal of Bone and Mineral Research, Vol. 15, No. 1, 2000, p. 120-128.

Research output: Contribution to journalArticle

Bianco, P, Riminucci, M, Majolagbe, A, Kuznetsov, SA, Collins, MT, Mankani, MH, Corsi, A, Bone, HG, Wientroub, S, Spiegel, AM, Fisher, LW & Gehron Robey, P 2000, 'Mutations of the GNAS1 gene, stromal cell dysfunction, and osteomalacic changes in non-McCune-Albright fibrous dysplasia of bone', Journal of Bone and Mineral Research, vol. 15, no. 1, pp. 120-128.
Bianco, P. ; Riminucci, M. ; Majolagbe, A. ; Kuznetsov, S. A. ; Collins, M. T. ; Mankani, M. H. ; Corsi, A. ; Bone, H. G. ; Wientroub, S. ; Spiegel, Allen M. ; Fisher, L. W. ; Gehron Robey, Pamela. / Mutations of the GNAS1 gene, stromal cell dysfunction, and osteomalacic changes in non-McCune-Albright fibrous dysplasia of bone. In: Journal of Bone and Mineral Research. 2000 ; Vol. 15, No. 1. pp. 120-128.
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AU - Riminucci, M.

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AU - Kuznetsov, S. A.

AU - Collins, M. T.

AU - Mankani, M. H.

AU - Corsi, A.

AU - Bone, H. G.

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