TY - JOUR
T1 - Mosaic Activating Mutations in FGFR1 Cause Encephalocraniocutaneous Lipomatosis
AU - Bennett, James T.
AU - Tan, Tiong Yang
AU - Alcantara, Diana
AU - Tétrault, Martine
AU - Timms, Andrew E.
AU - Jensen, Dana
AU - Collins, Sarah
AU - Nowaczyk, Malgorzata J.M.
AU - Lindhurst, Marjorie J.
AU - Christensen, Katherine M.
AU - Braddock, Stephen R.
AU - Brandling-Bennett, Heather
AU - Hennekam, Raoul C M
AU - Chung, Brian
AU - Lehman, Anna
AU - Su, John
AU - Ng, Suyuen
AU - Amor, David J
AU - Majewski, Jacek
AU - Biesecker, Les G.
AU - Boycott, Kym M.
AU - Dobyns, William B.
AU - O'Driscoll, Mark
AU - Moog, Ute
AU - McDonell, Laura M.
PY - 2016/3/3
Y1 - 2016/3/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84959911385&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2016.02.006
DO - 10.1016/j.ajhg.2016.02.006
M3 - Article
C2 - 26942290
AN - SCOPUS:84959911385
SN - 0002-9297
VL - 98
SP - 579
EP - 587
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 3
ER -