Mosaic Activating Mutations in FGFR1 Cause Encephalocraniocutaneous Lipomatosis.

Abstract:

: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.

journal_name

Am J Hum Genet

authors

Bennett JT,Tan TY,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 S,Amor DJ,University of Washington Ce

doi

10.1016/j.ajhg.2016.02.006

subject

Has Abstract

pub_date

2016-03-03 00:00:00

pages

579-587

issue

3

eissn

0002-9297

issn

1537-6605

pii

S0002-9297(16)00057-4

journal_volume

98

pub_type

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