MUTATIONS IN LMX1B CAUSE ABNORMAL SKELETAL PATTERNING AND RENAL DYSPLASIA IN NAIL-PATELLA SYNDROME

The LIM-homeodomain protein Lmx1b plays a central role in dorso-ventra l patterning of the vertebrate limb(1). Targeted disruption of Lmx1b r esults in skeletal defects including hypoplastic nails, absent patella e and a unique form of renal dysplasia (see accompanying manuscript by Fl. Chen et al.; ref. 2). These features are reminiscent of the domin antly inherited skeletal malformation nail patella syndrome (NPS). We show that LMX1B maps to the NPS locus and that three independent NPS p atients carry de novo heterozygous mutations in this gene. Functional studies show that one of these mutations disrupts sequence-specific DN A binding, while the other two mutations result in premature terminati on of translation. These data demonstrate a unique role for LMX1B in r enal development and in patterning of the skeletal system, and suggest that alteration of Lmx1b/LMX1B function in mice and humans results in similar phenotypes, Furthermore, we provide evidence for the first de scribed mutations in a LIM-homeodomain protein which account for an in herited form of abnormal skeletal patterning and renal failure.