Mutations in LMX1B cause abnormal skeletal patterning and renal dysplasia in nail patella syndrome

The LIM-homeodomain protein Lmxlb plays a central role in dorso-ventral patterning of the vertebrate limb1. Targeted disruption of Lmxlb results in skeletal defects including hypoplas-tic

nails, absent patellae and a unique form of renal dysplasia (see accompanying manuscript by H. Chen et al.; ref. 2). These features are reminiscent of the dominantly inherited skeletal

malformation nail patella syndrome (NFS). We show that LMX1B maps to the NFS locus and that three independent NFS patients carry de novo heterozygous mutations in this gene. Functional

studies show that one of these mutations disrupts sequence-specific DNA binding, while the other two mutations result in premature termination of translation. These data demonstrate a unique

role for LMX1B in renal development and in patterning of the skeletal system, and suggest that alteration of Lmxlb/LMX1B function in mice and humans results in similar phenotypes.

Furthermore, we provide evidence for the first described mutations in a LIM-homeodomain protein which account for an inherited form of abnormal skeletal patterning and renal failure.

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