Nail-patella syndrome (NPS) is characterized by dysplasia of the nail and bone abnormalities such as aplastic or hypoplastic patella, frequently associated with nephropathy. NPS is caused by heterozygous mutations in the LMX1B gene, encoding a member of the LIM homeodomain protein family. Gene analysis in NPS has so far disclosed that haploinsufficiency of LMX1B leads to the clinical manifestation of NPS. In this study, we evaluated two families with NPS. Direct sequencing analysis revealed Family 1 and Family 2 were heterozygous for the splice site mutations, c.140-1G>C (IVS1-1G>C) and c.326+1G>C (IVS2+1G>C), in LMX1B, respectively. To identify the mechanism of pathogenesis, we performed reverse transcriptase-PCR of cDNAs extracted from the dorsal skins of their thumbs, which showed normal and shortened PCR products in both samples. Intriguingly sequencing of the shortened PCR products revealed the same splice variant with deletion of exon 2, leading to a frameshift and a downstream premature termination codon (p.Asp49Serfs*18). Our data confirm that NPS is caused by haploinsufficiency of LMX1B.

Two families of nail-patella syndrome with novel splice site mutations in the LMX1B gene