Nail- patella syndrome (NPS) is an autosomal dominant disease characterized by dysplastic nails, absent or hypoplastic patellae, elbow dysplasia, and nephro pathy. Recently, it was shown that NPS is the result of heterozygous mutations i n the LIM- homeodomain gene, LMX1B. Subsequently, many mutations of the LMX1B g ene have been reported in NPS patients. However, functional analyses of the muta nt proteins have been performed in only a few mutations. Furthermore, the mechan isms of dominant inheritance in humans have not been established. In the present study, we analyzed the LMX1B gene in three Japanese patients with NPS and ident ified two novel mutations, 6 nucleotide deletion (Δ 246N 247Q) and V242L. These two mutations are located in the homeodomain of LMX1B. Functional analyses of t he LMX1B mutants revealed that these mutants had diminished transcriptional activity and had lost DNA binding ability. Furthermore, we demonstrated that each mutant did not manifest a dominant- negative effect on the transcriptional activity of wild- type LMX1B. These results suggested that NPS is caused by lo ss- of- function mutations of LMX1B, and haploin sufficiency of LMX1B should b e the predominant pathogenesis of NPS in humans.
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