LMX1B haploinsufficiency due to variants in the 5'UTR as a cause of Nail-Patella syndrome

Nail-Patella syndrome (NPS) is a rare autosomal dominant condition due to haploinsufficiency of LMX1B, caused by loss-of-function variants affecting the coding sequence, or partial/whole deletions of the gene. In here, we describe two familial cases of NPS, carrying novel variants of the LMX1B 5’UTR region (−174C>T and −226G>A). To verify their pathogenic role, we carried out a functional characterization, both by reporter gene assays in heterologous systems and in patient’s derived cells. We demonstrated that both variants impair LMX1B expression at post-transcriptional level. They introduce two upstream open reading frames (uORFs), out-of-frame with the main LMX1B coding sequence, generating transcripts detected by the non-sense mediated decay (NMD). We also demonstrated that the escape of the altered mRNA from NMD, if any, may lead to the synthesis of an aberrant LMX1B protein.