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bioRxiv · 10.1101/2025.11.19.689218

LAMA5 deficiency disrupts ECM-WNT crosstalk in chondrogenesis and contributes to idiopathic short stature

Schulz, A.·Brockmann, E. M.·Uebe, S.·Ekici, A. B.·Thiel, C. T.
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Abstract

Idiopathic short stature (ISS) affects 2%-3% of the population and is genetically heterogeneous, with emerging evidence implicating the extracellular matrix (ECM) of the growth plate. We identify LAMA5, encoding laminin-5, as a candidate ISS gene, with rare heterozygous variants present in 1.2% of affected individuals. To define its functional role, we generated CRISPR/Cas9-mediated LAMA5-knockout (KO) urine-derived stem cells (USCs) and induced chondrogenic differentiation in two- and three-dimensional culture systems. Loss of LAMA5 impaired chondrogenesis, with disruption of cell-cell junction programs and abnormal architecture of chondrogenic spheroids. Bulk RNA sequencing combined with weighted gene co-expression network analysis revealed WNT7A and FLI1 as key dysregulated genes within the module most strongly associated with the KO phenotype. Gene Ontology enrichment of this module highlighted embryonic limb morphogenesis as the top biological process, and WNT7A was assigned to canonical WNT signaling. Pharmacologic activation of WNT signaling using lithium chloride (LiCl) partially restored expression of WNT7A, FLI1, TFAP2A, GRHL2, and PITX1 toward wild-type levels, indicating that attenuated WNT activity is a principal downstream consequence of LAMA5 deficiency. Consistent with this, we identified an individual with ISS carrying a heterozygous PITX1 missense variant, supporting convergence of ECM (LAMA5) and transcriptional (PITX1) perturbations on a shared WNT-centered limb-morphogenesis network. Together, these findings demonstrate that laminin-5 is required for proper ECM-WNT signaling integration during human chondrogenesis and suggest that dysregulated WNT activity represents a mechanistic link between LAMA5 dysfunction and impaired endochondral growth. Partial rescue by WNT pathway re-activation highlights a potentially targetable downstream mechanism in ISS pathogenesis.

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Schulz, A., Brockmann, E. M., Uebe, S., Ekici, A. B., Thiel, C. T.. 2025-11-19. LAMA5 deficiency disrupts ECM-WNT crosstalk in chondrogenesis and contributes to idiopathic short stature. https://doi.org/10.1101/2025.11.19.689218

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