Multilineage somatic activating mutations in HRAS and NRAS cause mosaic cutaneous and skeletal lesions, elevated FGF23 and hypophosphatemia
| Autor: | Lori C. Guthrie, Patrick K. Kelley, Young H. Lim, Richard P. Lifton, Michael Gottschalk, Michael T. Collins, John D. Overton, Ann Maruri, Edward W. Cowen, Moise L. Levy, Harald Jüppner, Shrikant Mane, Cynthia M. C. Deklotz, William A. Gahl, Rachel I Gafni, Jeffrey S. Sugarman, Keith A. Choate, Nisan Bhattacharyya, Diana Ovejero, Alison M. Boyce, Erin C. Loring, Lawrence F. Eichenfield, Cynthia J. Tifft, Gretchen Golas |
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| Rok vydání: | 2013 |
| Předmět: |
Neuroblastoma RAS viral oncogene homolog
Male Kidney Disease Skin Neoplasms Hypophosphatemia urologic and male genital diseases Medical and Health Sciences GTP Phosphohydrolases 2.1 Biological and endogenous factors Developmental Exome Aetiology Child Genetics (clinical) Skin Genetics & Heredity Osteomalacia Nevus Pigmented integumentary system Gene Expression Regulation Developmental General Medicine Articles Melanocytic nevus Biological Sciences Female Activating RAS Mutation Sequence Analysis Adolescent 1.1 Normal biological development and functioning Biology Proto-Oncogene Proteins p21(ras) Rare Diseases Congenital melanocytic nevus Pigmented Underpinning research medicine Genetics Nevus Humans HRAS Molecular Biology Membrane Proteins DNA Sequence Analysis DNA medicine.disease Fibroblast Growth Factors stomatognathic diseases Fibroblast Growth Factor-23 Gene Expression Regulation Mutation Cancer research |
| Zdroj: | Human molecular genetics, vol 23, iss 2 |
| ISSN: | 1460-2083 |
| Popis: | Pathologically elevated serum levels of fibroblast growth factor-23 (FGF23), a bone-derived hormone that regulates phosphorus homeostasis, result in renal phosphate wasting and lead to rickets or osteomalacia. Rarely, elevated serum FGF23 levels are found in association with mosaic cutaneous disorders that affect large proportions of the skin and appear in patterns corresponding to the migration of ectodermal progenitors. The cause and source of elevated serum FGF23 is unknown. In those conditions, such as epidermal and large congenital melanocytic nevi, skin lesions are variably associated with other abnormalities in the eye, brain and vasculature. The wide distribution of involved tissues and the appearance of multiple segmental skin and bone lesions suggest that these conditions result from early embryonic somatic mutations. We report five such cases with elevated serum FGF23 and bone lesions, four with large epidermal nevi and one with a giant congenital melanocytic nevus. Exome sequencing of blood and affected skin tissue identified somatic activating mutations of HRAS or NRAS in each case without recurrent secondary mutation, and we further found that the same mutation is present in dysplastic bone. Our finding of somatic activating RAS mutation in bone, the endogenous source of FGF23, provides the first evidence that elevated serum FGF23 levels, hypophosphatemia and osteomalacia are associated with pathologic Ras activation and may provide insight in the heretofore limited understanding of the regulation of FGF23. |
| Databáze: | OpenAIRE |
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