Patient-derived LMX1B variant produces tissue-specific nail-patella syndrome features in knock-in mice

Researchers have generated a CRISPR/Cas9 knock-in mouse model carrying the R252Q amino acid substitution in LMX1B, the transcription factor gene whose pathogenic variants underlie nail-patella syndrome (NPS) in humans. The work is reported in a preprint posted to bioRxiv and has not yet been peer-reviewed.

Nail-patella syndrome is an autosomal dominant multisystem disorder characterised by dysplasia of the nails and kneecaps (patellae), along with variable extraskeletal manifestations including progressive nephropathy and glaucoma. In clinical practice, different LMX1B variants are sometimes associated with differing organ-system predominance — for instance, some families show predominantly renal disease with minimal skeletal features. The R252Q substitution corresponds to one such human variant associated with renal-predominant NPS.

Heterozygous mice were not reported to show a strong phenotype in the preliminary analysis described in the preprint lede. Homozygous knock-in mice were viable but showed marked growth retardation and severe bilateral ocular opacity — findings that differ from the renal-predominant phenotype observed in human carriers of the corresponding variant. The authors note that the mouse model nonetheless exhibited clear skeletal features.

The divergence between the human and mouse phenotypic profiles illustrates the well-recognised challenge of modelling tissue-specific genotype–phenotype relationships across species. The preprint offers a resource for researchers studying LMX1B biology and NPS pathophysiology, and may inform efforts to develop cellular or organoid models that better recapitulate the human renal phenotype. Full phenotypic characterisation, particularly of kidney histology, has not yet been reported.