FGFR4 p.Gly388Arg polymorphism in PBMCs of LAM patients: findings of a pilot study

Sinem Koc-Gunel; Amy L. Ryan; Melanie Winter; Thomas O. F. Wagner

doi:10.3389/fmed.2025.1544910

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FGFR4 p.Gly388Arg polymorphism in PBMCs of LAM patients: findings of a pilot study

Journal article

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FGFR4 p.Gly388Arg polymorphism in PBMCs of LAM patients: findings of a pilot study

Sinem Koc-Gunel, Amy L. Ryan, Melanie Winter and Thomas O. F. Wagner

Frontiers in medicine, Vol.12, 1544910

07/24/2025

DOI: 10.3389/fmed.2025.1544910

PMCID: PMC12328168

PMID: 40776927

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Abstract

Lymphangioleiomyomatosis (LAM) is a rare, progressive lung disease characterized by neoplastic-like proliferation of abnormal smooth muscle–like cells, primarily driven by mutations in the TSC2 gene. These mutations result in hyperactivation of the mTOR signaling pathway, leading to uncontrolled cell growth. However, additional genetic variants may modulate disease progression and severity. In this observational pilot study, we investigated the potential role of co-occurring variants. Peripheral blood mononuclear cells from seven sporadic LAM patients were analyzed using next-generation sequencing to identify potentially tumorigenic variants. The FGFR4 p.Gly388Arg gain-of-function polymorphism was identified in four patients, with allelic frequencies ranging from 49 to 99%. Patients with the variant exhibited significantly faster rates of lung function decline, as measured by FEV₁%, compared to those without the variant. Spatial transcriptomic analysis of LAM lung tissue revealed FGFR4 expression predominantly in alveolar fibroblasts and AT2 epithelial cells, key compartments in lung remodeling, while detection in PBMCs supports a potential systemic role. These preliminary findings support the hypothesis that FGFR4 mutations contribute to the systemic aspects of LAM, potentially exacerbating disease severity. They also highlight the need for larger, mechanistic studies to evaluate FGFR4 as a biomarker or therapeutic target. Overall, this study provides a hypothesis-generating framework for future investigations into the genetic drivers of LAM beyond TSC2 mutations.

lymphangioleiomyomatosis (LAM)

FGFR4 p.Gly388Arg polymorphism

peripheral blood mononuclear cells (PBMCs)

forced expiratory volume (FEV1%)

next-generation sequencing (NGS)

mTOR signaling pathway

genetic modifiers in rare lung disease

spatial transcriptomics

Details

Title: Subtitle: FGFR4 p.Gly388Arg polymorphism in PBMCs of LAM patients: findings of a pilot study
Creators: Sinem Koc-Gunel - University Hospital Frankfurt
Amy L. Ryan - University of Iowa
Melanie Winter - University Hospital Frankfurt
Thomas O. F. Wagner - University Hospital Frankfurt
Resource Type: Journal article
Publication Details: Frontiers in medicine, Vol.12, 1544910
DOI: 10.3389/fmed.2025.1544910
PMID: 40776927
PMCID: PMC12328168
NLM abbreviation: Front Med (Lausanne)
ISSN: 2296-858X
eISSN: 2296-858X
Publisher: FRONTIERS MEDIA SA
Grant note: German Research Foundation (DFG): KO5803/2-1 Federal Ministry for Research and Education Germany (BMBF): 01EO2102 Department of Internal Medicine, Goethe University Frankfurt
The author(s) declare that financial support was received for the research and/or publication of this article. This study was supported by the German Research Foundation (DFG) (grant no. KO5803/2-1 to SK-G), the Federal Ministry for Research and Education Germany (BMBF) (grant no. 01EO2102 to SK-G) and Departmental funds from the Department of Internal Medicine, Goethe University Frankfurt.
Language: English
Date published: 07/24/2025
Academic Unit: Anatomy and Cell Biology
Record Identifier: 9984927205002771

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