Evidence that FGFRL1 contributes to congenital diaphragmatic hernia development in humans

Abstract

Fibroblast growth factor receptor‐like 1 (FGFRL1) encodes a transmembrane protein that is related to fibroblast growth factor receptors but lacks an intercellular tyrosine kinase domain. in vitro studies suggest that FGFRL1 inhibits cell proliferation and promotes cell differentiation and cell adhesion. Mice that lack FGFRL1 die shortly after birth from respiratory distress and have abnormally thin diaphragms whose muscular hypoplasia allows the liver to protrude into the thoracic cavity. Haploinsufficiency of FGFRL1 has been hypothesized to contribute to the development of congenital diaphragmatic hernia (CDH) associated with Wolf‐Hirschhorn syndrome. However, data from both humans and mice suggest that disruption of one copy of FGFRL1 alone is insufficient to cause diaphragm defects. Here we report a female fetus with CDH whose 4p16.3 deletion allows us to refine the Wolf‐Hirschhorn syndrome CDH critical region to an approximately 1.9 Mb region that contains FGFRL1. We also report a male infant with isolated left‐sided diaphragm agenesis who carried compound heterozygous missense variants in FGFRL1. These cases provide additional evidence that deleterious FGFRL1 variants may contribute to the development of CDH in humans.

Identification of Piperazinyl–Difluoro-indene Derivatives Containing Pyridyl Groups as Potent FGFR Inhibitors against FGFR Mutant Tumor: Design, Synthesis, and Biological Evaluation

“…Tumor growth was monitored by measuring the dimensions of xenografts 3 times a week. The tumor volumes were calculated using the following formula: volume (mm 3 ) = 0.5 × longest tumor diameter × (shortest tumor diameter) 2 . Mouse body weight was also recorded three times weekly.…”

“…Fibroblast growth factor receptors (FGFRs) belong to the receptor tyrosine kinase family, and they include four highly conserved transmembrane receptors (FGFR1, FGFR2, FGFR3, and FGFR4) and a membrane-associated receptor lacking the intracellular domain (FGFRL1). , When different fibroblast growth factors (FGFs) bind to FGFRs, the FGFRs form dimers, leading to the intracellular phosphorylation of receptor kinase domains, thereby activating downstream signaling pathways, such as RAS-RaF-MEK-ERK, PLCγ-PKC, JAK-STAT, and PI3K-AKT signaling. − The FGF/FGFR signaling pathway plays crucial roles in cell proliferation and angiogenesis, embryonic and fetal development, tissue development, immune surveillance, and metabolism. However, abnormal activation of this signaling pathway, as induced by amplification, point mutations, translocation, and gene fusion, can lead to carcinogenesis. , FGFR alterations have been observed in several solid tumors, such as breast cancer, lung cancer, gastric cancer, urothelial carcinoma, liver cancer, bladder cancer, bile duct cancer, and endometrial adenocarcinoma. , To date, four FGFR inhibitors have been developed to treat solid tumors harboring FGFR alterations. , Erdafitinib ( 1 ), − pemigatinib ( 2 ), − infigratinib ( 3 ), , and futibatinib ( 4 ) , have been approved by the US Food and Drug Administration for the treatment of urothelial carcinoma harboring FGFR3 point mutations or fusion genes and cholangiocarcinoma harboring FGFR2 fusion genes or other rearrangements (Figure ).…”

“…Fibroblast growth factor receptors (FGFRs) belong to the receptor tyrosine kinase family, and they include four highly conserved transmembrane receptors (FGFR1, FGFR2, FGFR3, and FGFR4) and a membrane-associated receptor lacking the intracellular domain (FGFRL1). 1,2 When different fibroblast growth factors (FGFs) bind to FGFRs, the FGFRs form dimers, leading to the intracellular phosphorylation of receptor kinase domains, thereby activating downstream signaling pathways, such as RAS-RaF-MEK-ERK, PLCγ-PKC, JAK-STAT, and PI3K-AKT signaling. 3−5 The FGF/FGFR signaling pathway plays crucial roles in cell proliferation and angiogenesis, embryonic and fetal development, tissue development, immune surveillance, and metabolism.…”

The Role of De Novo Variants in Patients with Congenital Diaphragmatic Hernia

“…Less frequently described in association with CDH 4p16 deletions (Wolf-Hirschhorn syndrome) [ 28 , 29 ], comprising the CDH-associated gene FGFRL1 [ 30 ]; 22q11.2 deletion [ 31 ]; deletion and duplication of 17q12 [ 32 , 33 ], and 1q12 duplication [ 34 ]. Very rare CNVs in CDH patients have been described and comprehensively been reviewed by Wynn et al [ 18 ].…”