Mosaic Activating Mutations in FGFR1 Cause Encephalocraniocutaneous Lipomatosis.

TitleMosaic Activating Mutations in FGFR1 Cause Encephalocraniocutaneous Lipomatosis.
Publication TypeJournal Article
Year of Publication2016
AuthorsBennett, JT, Tan, TYang, Alcantara, D, Tétrault, M, Timms, AE, Jensen, D, Collins, S, Nowaczyk, MJM, Lindhurst, MJ, Christensen, KM, Braddock, SR, Brandling-Bennett, H, Hennekam, RCM, Chung, B, Lehman, A, Su, J, Ng, SY, Amor, DJ, Majewski, J, Biesecker, LG, Boycott, KM, Dobyns, WB, O'Driscoll, M, Moog, U, McDonell, LM
Corporate AuthorsUniversity of Washington Center for Mendelian Genomics, Care4Rare Canada Consortium
JournalAm J Hum Genet
Date Published2016 Mar 03
KeywordsAdolescent, Cell Line, Tumor, Central Nervous System Neoplasms, Child, Preschool, Exome, Eye, Eye Diseases, Female, Humans, Infant, Lipomatosis, Male, Mutation, Mutation, Missense, Neurocutaneous Syndromes, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, Receptor, Fibroblast Growth Factor, Type 1, Seizures, Sequence Analysis, DNA

Encephalocraniocutaneous lipomatosis (ECCL) is a sporadic condition characterized by ocular, cutaneous, and central nervous system anomalies. Key clinical features include a well-demarcated hairless fatty nevus on the scalp, benign ocular tumors, and central nervous system lipomas. Seizures, spasticity, and intellectual disability can be present, although affected individuals without seizures and with normal intellect have also been reported. Given the patchy and asymmetric nature of the malformations, ECCL has been hypothesized to be due to a post-zygotic, mosaic mutation. Despite phenotypic overlap with several other disorders associated with mutations in the RAS-MAPK and PI3K-AKT pathways, the molecular etiology of ECCL remains unknown. Using exome sequencing of DNA from multiple affected tissues from five unrelated individuals with ECCL, we identified two mosaic mutations, c.1638C>A (p.Asn546Lys) and c.1966A>G (p.Lys656Glu) within the tyrosine kinase domain of FGFR1, in two affected individuals each. These two residues are the most commonly mutated residues in FGFR1 in human cancers and are associated primarily with CNS tumors. Targeted resequencing of FGFR1 in multiple tissues from an independent cohort of individuals with ECCL identified one additional individual with a c.1638C>A (p.Asn546Lys) mutation in FGFR1. Functional studies of ECCL fibroblast cell lines show increased levels of phosphorylated FGFRs and phosphorylated FRS2, a direct substrate of FGFR1, as well as constitutive activation of RAS-MAPK signaling. In addition to identifying the molecular etiology of ECCL, our results support the emerging overlap between mosaic developmental disorders and tumorigenesis.

Alternate JournalAm. J. Hum. Genet.
PubMed ID26942290
PubMed Central IDPMC4800051
Grant ListU54 HG006493 / HG / NHGRI NIH HHS / United States
U54 HD083091 / HD / NICHD NIH HHS / United States
R01 NS092772 / NS / NINDS NIH HHS / United States
R01 HL130996 / HL / NHLBI NIH HHS / United States
1R01NS092772 / NS / NINDS NIH HHS / United States
U54HG006493 / HG / NHGRI NIH HHS / United States
/ / Intramural NIH HHS / United States
/ / Canadian Institutes of Health Research / Canada
/ / Cancer Research UK / United Kingdom
UM1 HG006493 / HG / NHGRI NIH HHS / United States