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Deficiency of the alpha-subunit of the stimulatory G protein and severe extraskeletal ossification
M C Eddy1, S M Jan De Beur, S M Yandow
1Center for Metabolic Bone Disease and Molecular Research, Shriners Hospital for Children, St. Louis, Missouri 63131, USA.
Insights
Progressive osseous heteroplasia (POH) and Albright hereditary osteodystrophy (AHO) may share a molecular basis. Reduced G protein alpha-subunit (Gsalpha) levels suggest Gsalpha deficiency may cause severe extraskeletal ossification.
Area of Science:
- Genetics
- Molecular Biology
- Endocrinology
Background:
- Progressive osseous heteroplasia (POH) is a rare genetic disorder causing extensive extraskeletal ossification.
- Albright hereditary osteodystrophy (AHO) is another rare disorder associated with hormone resistance and skeletal abnormalities.
Observation:
- Two unrelated girls presented with clinical, radiographic, and histological features of both POH and AHO.
- One patient had mild brachydactyly, while the other exhibited brachydactyly, obesity, and resistance to thyrotropin and parathyroid hormone (PTH).
Findings:
- Reduced levels of the G protein alpha-subunit (Gsalpha) were observed in erythrocyte membranes of both patients.
- A nonsense mutation (Q12X) in the GNAS1 gene was identified in one patient, confirming Gsalpha deficiency.
Implications:
- The co-occurrence of POH and AHO suggests a shared molecular basis and pathogenesis.
- Severe extraskeletal ossification may be an additional manifestation of Gsalpha deficiency, broadening the phenotypic spectrum of GNAS1-related disorders.
Abstract:
Progressive osseous heteroplasia (POH) is a rare disorder characterized by dermal ossification beginning in infancy followed by increasing and extensive bone formation in deep muscle and fascia. We describe two unrelated girls with typical clinical, radiographic, and histological features of POH who also have findings of another uncommon heritable disorder, Albright hereditary osteodystrophy (AHO). One patient has mild brachydactyly but no endocrinopathy, whereas the other manifests brachydactyly, obesity, and target tissue resistance to thyrotropin and parathyroid hormone (PTH). Levels of the alpha-subunit of the G protein (Gsalpha) were reduced in erythrocyte membranes from both girls and a nonsense mutation (Q12X) in exon 1 of the GNAS1 gene was identified in genomic DNA from the mildly affected patient. Features of POH and AHO in two individuals suggest that these conditions share a similar molecular basis and pathogenesis and that isolated severe extraskeletal ossification may be another manifestation of Gsalpha deficiency.
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