Phenotypic spectrum of FGF10-related disorders: a systematic review

Abstract

FGF10, as an FGFR2b-specific ligand, plays a crucial role during cell proliferation, multi-organ development, and tissue injury repair. The developmental importance of FGF10 has been emphasized by the identification of FGF10 abnormalities in human congenital disorders affecting different organs and systems. Single-nucleotide variants in FGF10 or FGF10-involving copy-number variant deletions have been reported in families with lacrimo-auriculo-dento-digital syndrome, aplasia of the lacrimal and salivary glands, or lethal lung developmental disorders. Abnormalities involving FGF10 have also been implicated in cleft lip and palate, myopia, or congenital heart disease. However, the exact developmental role of FGF10 and large phenotypic heterogeneity associated with FGF10 disruption remain incompletely understood. Here, we review human and animal studies and summarize the data on FGF10 mechanism of action, expression, multi-organ function, as well as its variants and their usefulness for clinicians and researchers.

Keywords: Congenital diseases; FGF10 deficiency; Pulmonary diseases.

Figure 1. A simplified scheme of the FGF10/FGFR2b activation.

Numbers I-III indicate immunoglobulin-like subdomains of the FGFR2b extracellular domain, with the FGF10 ligand and HSPG binding sites between subdomains II and III. In the tyrosine kinase domains, the purple square box indicates the phosphorylation sites required for activation of the FGF receptor substrate 2 α (FRS2 α), growth factor receptor-bound protein 2 (GRB2) and phospholipase C gamma 1 (PLC γ1). After phosphorylation of PLC γ1, calcium is released and protein kinase C (PKC) is enabled. Activated FRS2 α and GRB2 lead to activation of RAS-MAPK and PI3K-AKT signaling pathways.

Figure 2. Schematic representation of the FGF10 protein.

Blue, grey, and dark green boxes indicate signal peptide, the FGF10 domain, and glycolysation sites, respectively. Variants identified in patients with lethal lung developmental disorders (LLDD), lacrimo-auriculo-dento-digital syndrome (LADD), aplasia of the lacrimal and salivary glands (ALSG), and risk of chronic obstructive pulmonary disease (COPD) are shown as lollipops and are represented in orange, light green, dark blue, and yellow, respectively. The number of circles in the lollipop represent a number of individuals with a particular variant and two-colored circles indicate patients affected by two different conditions.