G2Cdb::Human Disease report

Disease id
D00000112
Name
Platelike osteoma cutis
Nervous system disease
no

Genes (1)

Gene Name/Description Mutations Found Literature Mutations Type Genetic association?
G00001473 GNAS
GNAS complex locus
Y (11092389) Deletion (D) Y

References

  • GNAS1 mutation and Cbfa1 misexpression in a child with severe congenital platelike osteoma cutis.

    Yeh GL, Mathur S, Wivel A, Li M, Gannon FH, Ulied A, Audi L, Olmstead EA, Kaplan FS and Shore EM

    Department of Orthopaedic Surgery, University of Pennsylvania, School of Medicine, Philadelphia 19104-6081, USA.

    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.

    Funded by: NIAMS NIH HHS: 1-RO1-AR46831-01, 2-RO1-AR41916-04, R01 AR041916, R01 AR046831

    Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 2000;15;11;2063-73

Literature (1)

Pubmed - human_disease

  • GNAS1 mutation and Cbfa1 misexpression in a child with severe congenital platelike osteoma cutis.

    Yeh GL, Mathur S, Wivel A, Li M, Gannon FH, Ulied A, Audi L, Olmstead EA, Kaplan FS and Shore EM

    Department of Orthopaedic Surgery, University of Pennsylvania, School of Medicine, Philadelphia 19104-6081, USA.

    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.

    Funded by: NIAMS NIH HHS: 1-RO1-AR46831-01, 2-RO1-AR41916-04, R01 AR041916, R01 AR046831

    Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 2000;15;11;2063-73

© G2C 2014. The Genes to Cognition Programme received funding from The Wellcome Trust and the EU FP7 Framework Programmes:
EUROSPIN (FP7-HEALTH-241498), SynSys (FP7-HEALTH-242167) and GENCODYS (FP7-HEALTH-241995).

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