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GNAS1 mutation and Cbfa1 misexpression in a child with severe congenital platelike osteoma cutis.
J Bone Miner Res. 2000 Nov; 15(11):2063-73.JB

Abstract

We evaluated a 7-year-old girl with severe platelike osteoma cutis (POC), a variant of progressive osseous heteroplasia (POH). The child had congenital heterotopic ossification of dermis and subcutaneous fat that progressed to involve deep skeletal muscles of the face, scalp, and eyes. Although involvement of skeletal muscle is a prominent feature of POH, heterotopic ossification has not been observed in the head, face, or extraocular muscles. The cutaneous ossification in this patient was suggestive of Albright hereditary osteodystrophy (AHO); however, none of the other characteristic features of AHO were expressed. Inactivating mutations of the GNAS1 gene, which encodes the alpha-subunit of the stimulatory G protein of adenylyl cyclase, is the cause of AHO. Mutational analysis of GNAS1 using genomic DNA of peripheral blood and of lesional and nonlesional tissue from our patient revealed a heterozygous 4-base pair (bp) deletion in exon 7, identical to mutations that have been found in some AHO patients. This 4-bp deletion in GNAS1 predicts a protein reading frameshift leading to 13 incorrect amino acids followed by a premature stop codon. To investigate pathways of osteogenesis by which GNAS1 may mediate its effects, we examined the expression of the obligate osteogenic transcription factor Cbfa1/RUNX2 in lesional and uninvolved dermal fibroblasts from our patient and discovered expression of bone-specific Cbfa1 messenger RNA (mRNA) in both cell types. These findings document severe heterotopic ossification in the absence of AHO features caused by an inactivating GNAS1 mutation and establish the GNAS1 gene as the leading candidate gene for POH.

Authors+Show Affiliations

Department of Orthopaedic Surgery, University of Pennsylvania, School of Medicine, Philadelphia 19104-6081, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Case Reports
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

11092389

Citation

Yeh, G L., et al. "GNAS1 Mutation and Cbfa1 Misexpression in a Child With Severe Congenital Platelike Osteoma Cutis." Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research, vol. 15, no. 11, 2000, pp. 2063-73.
Yeh GL, Mathur S, Wivel A, et al. GNAS1 mutation and Cbfa1 misexpression in a child with severe congenital platelike osteoma cutis. J Bone Miner Res. 2000;15(11):2063-73.
Yeh, G. L., Mathur, S., Wivel, A., Li, M., Gannon, F. H., Ulied, A., Audi, L., Olmstead, E. A., Kaplan, F. S., & Shore, E. M. (2000). GNAS1 mutation and Cbfa1 misexpression in a child with severe congenital platelike osteoma cutis. Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research, 15(11), 2063-73.
Yeh GL, et al. GNAS1 Mutation and Cbfa1 Misexpression in a Child With Severe Congenital Platelike Osteoma Cutis. J Bone Miner Res. 2000;15(11):2063-73. PubMed PMID: 11092389.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - GNAS1 mutation and Cbfa1 misexpression in a child with severe congenital platelike osteoma cutis. AU - Yeh,G L, AU - Mathur,S, AU - Wivel,A, AU - Li,M, AU - Gannon,F H, AU - Ulied,A, AU - Audi,L, AU - Olmstead,E A, AU - Kaplan,F S, AU - Shore,E M, PY - 2000/11/25/pubmed PY - 2001/6/2/medline PY - 2000/11/25/entrez SP - 2063 EP - 73 JF - Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research JO - J. Bone Miner. Res. VL - 15 IS - 11 N2 - We evaluated a 7-year-old girl with severe platelike osteoma cutis (POC), a variant of progressive osseous heteroplasia (POH). The child had congenital heterotopic ossification of dermis and subcutaneous fat that progressed to involve deep skeletal muscles of the face, scalp, and eyes. Although involvement of skeletal muscle is a prominent feature of POH, heterotopic ossification has not been observed in the head, face, or extraocular muscles. The cutaneous ossification in this patient was suggestive of Albright hereditary osteodystrophy (AHO); however, none of the other characteristic features of AHO were expressed. Inactivating mutations of the GNAS1 gene, which encodes the alpha-subunit of the stimulatory G protein of adenylyl cyclase, is the cause of AHO. Mutational analysis of GNAS1 using genomic DNA of peripheral blood and of lesional and nonlesional tissue from our patient revealed a heterozygous 4-base pair (bp) deletion in exon 7, identical to mutations that have been found in some AHO patients. This 4-bp deletion in GNAS1 predicts a protein reading frameshift leading to 13 incorrect amino acids followed by a premature stop codon. To investigate pathways of osteogenesis by which GNAS1 may mediate its effects, we examined the expression of the obligate osteogenic transcription factor Cbfa1/RUNX2 in lesional and uninvolved dermal fibroblasts from our patient and discovered expression of bone-specific Cbfa1 messenger RNA (mRNA) in both cell types. These findings document severe heterotopic ossification in the absence of AHO features caused by an inactivating GNAS1 mutation and establish the GNAS1 gene as the leading candidate gene for POH. SN - 0884-0431 UR - https://www.unboundmedicine.com/medline/citation/11092389/GNAS1_mutation_and_Cbfa1_misexpression_in_a_child_with_severe_congenital_platelike_osteoma_cutis_ L2 - https://doi.org/10.1359/jbmr.2000.15.11.2063 DB - PRIME DP - Unbound Medicine ER -