¹Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

Correspondence: Dr EMHF Bongers, Department of Human Genetics 849, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB, Nijmegen, The Netherlands. Tel: +31 24 3613946; Fax +31 24 3668753; E-mail: E.Bongers@antrg.umcn.nl

Received 1 November 2007; Revised 29 February 2008; Accepted 18 March 2008; Published online 16 April 2008.

Abstract

Heterozygous mutations in the LMX1B gene cause nail patella syndrome (NPS) that is associated with nail and skeletal malformations, nephropathy, and glaucoma. Previous phenotype studies of Lmx1b null mice revealed dorsal limb and renal anomalies similar to human NPS, which contributed to the identification of heterozygous mutations in this LIM-homeodomain protein LMX1B as the genetic defect responsible for NPS. Despite advanced insight into the role of the Lmx1b transcription factor in a broad range of animal developmental programs, the pathogenic mechanism underlying dominant inheritance of NPS in man remained unclear. Here, we describe for the first time the detection of two entire LMX1B gene deletions and one smaller exonic LMX1B deletion by multiplex ligation-dependent probe amplification (MLPA) in a series of eight unrelated families with classical features of NPS in whom no pathogenic LMX1B mutation was found by sequence analysis. The identification of entire LMX1B deletions strongly confirms that haploinsufficiency is the principal pathogenetic mechanism of NPS and suggests a difference in dosage sensitivity for this gene between mice and man.