1. ¹Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
2. ²Department of Internal Medicine, Radboud University Nijmegen Medical Centre, The Netherlands
3. ³Department of Paediatric Nephrology, Radboud University Nijmegen Medical Centre, The Netherlands
4. ⁴Department of Radiology, Radboud University Nijmegen Medical Centre, The Netherlands
5. ⁵Department of Otorhinolaryngology, Radboud University Nijmegen Medical Centre, The Netherlands
6. ⁶Department of Ophthalmology, Radboud University Nijmegen Medical Centre, The Netherlands
7. ⁷Department of Medical Psychology, Radboud University Nijmegen Medical Centre, The Netherlands
8. ⁸Department of Medical Technology Assessment, Radboud University Nijmegen Medical Centre, The Netherlands
9. ⁹Department of Epidemiology and Biostatistics, Radboud University Nijmegen, Nijmegen, The Netherlands
10. ¹⁰Department of Orthopaedic Surgery, Radboud University Nijmegen Medical Centre, The Netherlands

Correspondence: Professor NVAM Knoers, Department of Human Genetics, Radboud University Nijmegen Medical Centre, Geert Grooteplein 10, PO Box 9101, 6500 HB Nijmegen, The Netherlands. Tel: +31 24 3613946; Fax: +31 24 3565026; E-mail: n.knoers@antrg.umcn.nl

Received 7 February 2005; Revised 18 April 2005; Accepted 20 April 2005; Published online 1 June 2005.

Abstract

Nail-patella syndrome (NPS) is characterized by developmental defects of dorsal limb structures, nephropathy, and glaucoma and is caused by heterozygous mutations in the LIM homeodomain transcription factor LMX1B. In order to identify possible genotype–phenotype correlations, we performed LMX1B mutation analysis and comprehensive investigations of limb, renal, ocular, and audiological characteristics in 106 subjects from 32 NPS families. Remarkable phenotypic variability at the individual, intrafamilial, and interfamilial level was observed for different NPS manifestations. Quantitative urinanalysis revealed proteinuria in 21.3% of individuals. Microalbuminuria was detected in 21.7% of subjects without overt proteinuria. Interestingly, nephropathy appeared significantly more frequent in females. A significant association was established between the presence of clinically relevant renal involvement in an NPS patient and a positive family history of nephropathy. We identified normal-tension glaucoma (NTG) and sensorineural hearing impairment as new symptoms associated with NPS. Sequencing of LMX1B revealed 18 different mutations, including six novel variants, in 28 families. Individuals with an LMX1B mutation located in the homeodomain showed significantly more frequent and higher values of proteinuria compared to subjects carrying mutations in the LIM domains. No clear genotype–phenotype association was apparent for extrarenal manifestations. This is the first study indicating that family history of nephropathy and mutation location might be important in precipitating individual risks for developing NPS renal disease. We suggest that the NPS phenotype is broader than previously described and that NTG and hearing impairment are part of NPS. Further studies on modifier factors are needed to understand the mechanisms underlying phenotypic heterogeneity.