Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027960 (mole)
 21,279 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

FGFRL1 is a member of the fibroblast growth factor receptor (FGFR) family. Similar to the classical receptors FGFR1-FGFR4, it contains three extracellular Ig-like domains and a single transmembrane domain. However, it lacks the intracellular tyrosine kinase domain that would be required for signal transduction, but instead contains a short intracellular tail with a peculiar histidine-rich motif. This motif has been conserved during evolution from mollusks to echinoderms and vertebrates. Only the sequences of FgfrL1 from a few rodents diverge at the C-terminal region from the canonical sequence, as they appear to have suffered a frameshift mutation within the histidine-rich motif. This mutation is observed in mouse, rat and hamster, but not in the closely related rodents mole rat (Nannospalax) and jerboa (Jaculus), suggesting that it has occurred after branching of the Muridae and Cricetidae from the Dipodidae and Spalacidae. The consequence of the frameshift is a deletion of a few histidine residues and an extension of the C-terminus by about 40 unrelated amino acids. A similar frameshift mutation has also been observed in a human patient with a craniosynostosis syndrome as well as in several patients with colorectal cancer and bladder tumors, suggesting that the histidine-rich motif is prone to mutation. The reason why this motif was conserved during evolution in most species, but not in mice, is not clear.
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PMID:Phylogenetic analysis of receptor FgfrL1 shows divergence of the C-terminal end in rodents. 2593 85

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.
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PMID:Mosaic Activating Mutations in FGFR1 Cause Encephalocraniocutaneous Lipomatosis. 2694 90

A 5-year-old boy presented with worsening headaches for 3 months. On examination, he was found to have a hairless fatty tissue nevus of the scalp (nevus psiloliparus), subcutaneous soft tissue masses on the right side of his face, neck, mandible and right buttock and epibulbar dermoid of the right eye (choristoma) (). Magnetic resonance imaging revealed a large suprasellar mass, which was debulked and found to be a pilocytic astrocytoma. Testing was not performed for the BRAF/KIAA1549 fusion or BRAFV600E mutation. Seven years later, he was started on adjuvant chemotherapy for gradual tumor progression. Over the ensuing 3 years, he had further disease progression despite treatment with 3 frontline chemotherapy regimens: vinblastine, carboplatin/vincristine, and irinotecan/bevacizumab. Targeted sequencing of tissue from the right gluteal mass, revealed a mosaic activating FGFR1 c.1966A>G (p.Lys656Glu) mutation, absent in normal left gluteal tissue, confirming the diagnosis of encephalocraniocutaneous lipomatosis (ECCL), belonging to the family of RASopathies (including neurofibromatosis type I, Noonan syndrome, Costello syndrome), with constitutive activation of the mitogen-activated protein kinase (MAPK) pathway, and an increased risk of developing neoplasms. He was started on trametinib, a MEK inhibitor, off-label, targeting the MAPK pathway downstream from FGFR1, with stable tumor size at last follow-up, after 6 months on therapy.
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PMID:Encephalocraniocutaneous Lipomatosis. 2968 47

BACKGROUND Encephalocraniocutaneous lipomatosis is a rare neurocutaneous disorder characterized by cutaneous, ocular, and central nervous system anomalies; its molecular etiology was recently identified. This report describes the surgical treatment and genetic characterization of a giant ocular lipodermoid cyst secondary to encephalocraniocutaneous lipomatosis. CASE REPORT An 11-year-old girl with past medical history of absence seizures presented with a reddish protruding mass in her right eye involving the temporal conjunctiva and the peripheral temporal cornea; eyelid closure was not possible due to mass protrusion. She also presented skin tags at the level of the external canthus and 3 alopecic areas at the level of the scalp compatible with nevus psiloliparus. No family history was reported. A dermoid cyst was suspected and excisional biopsy was performed under general anesthesia. A large conjunctival and lamellar corneoscleral resection was done, followed by a corneal tectonic graft. Molecular analysis was carried out, including PCR and Sanger sequencing on DNA obtained from the mass. After surgery, the patient achieved complete eyelid closure, reduction of ocular surface symptoms, and improved aesthetic appearance. Histological analysis confirmed a lipodermoid cyst; genetic tests confirmed a mosaic activating mutation in FGFR1 (c.1638C>A, p.Asn546Lys). The diagnosis was encephalocraniocutaneous lipomatosis. CONCLUSIONS ECCL is a rare condition; an accurate diagnosis comprising clinical and genetic aspects can facilitate the monitoring of possible complications, improve the multidisciplinary treatment, and provide valuable information for future therapy developments. In this case, the patient's quality of life improved significantly, ocular symptoms disappeared, and a good esthetic appearance was achieved.
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PMID:Giant Ocular Lipodermoid Cyst in Encephalocraniocutaneous Lipomatosis: Surgical Treatment and Genetic Analysis. 3164 34