A patient-derived LMX1B variant causes tissue-specific manifestations of nail-patella syndrome in mice

Abstract

Nail-patella syndrome (NPS) is a multisystem disorder caused by pathogenic variants in LMX1B and is characterized by dysplasia of the nails and patellae as well as extraskeletal complications such as progressive nephropathy and glaucoma. We generated a CRISPR/Cas9 knock-in mouse carrying the R252Q substitution, corresponding to a human LMX1B variant associated with renal-predominant disease. Phenotypic analysis revealed that homozygous mice were viable, but they displayed marked growth retardation and severe bilateral ocular opacity. Interestingly, while this model exhibited clear skeletal and ocular defects, the renal phenotype was relatively mild, although increased urinary albumin excretion, focal glomerular basement membrane abnormalities, and subtle changes in renal gene expression were detected. Beyond the classical NPS hallmarks, mutant mice also displayed midbrain morphological abnormalities, suggesting broader developmental consequences of this LMX1B variant. This patient-derived variant model not only recapitulates the pleiotropic features of NPS but also demonstrates organ-specific susceptibility to the R252Q substitution, providing a foundation for elucidating the complex molecular mechanisms underlying multisystem disease. Author Summary Predicting how a disease-associated variant will affect different organs remains a major challenge. Variants in the same gene can produce different combinations and severities of symptoms. We studied a particular variant of LMX1B that is predominantly associated with kidney disease in patients by generating mice with the corresponding variant in their Lmx1b gene. Homozygous mice developed prominent abnormalities of the eyes, kneecap, and midbrain, whereas kidney involvement was comparatively mild. Thus, the mice displayed several features of nail-patella syndrome, although the relative involvement of different organs differed from the kidney-predominant presentation reported in patients carrying this variant. We also found that the altered LMX1B protein retained partial gene-regulatory activity rather than being completely inactive. Together, our findings show that the effects of an LMX1B variant cannot be predicted from its residual activity alone. Instead, the susceptibility of each organ may depend on the cellular and genetic context in which the variant acts.