Nail-Patella Syndrome

Nail-patella syndrome is an autosomal dominant disorder characterized by dyplasia of finger nails, skeletal anomalies, and, frequently, renal disease. It has recently been shown that this disorder is caused by putative loss-of-function mutations in a transcription factor (LMX1B) belonging to the LIMhomeodomain family, members of which are known to be important for pattern formation during development. A cohort of eight Dutch NPS families were screened for mutations in the LMX1B gene; seven different mutations, including one novel variant, were identified. Three of the mutations are very likely to result in truncated LMX1B proteins, three are predicted to influence sequence-specific DNA binding, and one is presumed to prevent the formation of a stable protein by abolishing the Zn(II) binding site of the protein. Although there was a remarkable high incidence of renal disease in one of the families, the nephropathy was not seen in all affected family members and the severity of renal impairment varied significantly among the patients. This indicates that the incidence and severity of nephropathy within this family cannot be attributed to the LMX1B genotype. In addition, evidence of a correlation between other characteristics of the NPS phenotype and specific mutations has not been found. Nail-patella syndrome (NPS) (MIM 161200), also known as hereditary osteo-onychodysplasia, is a rare autosomal dominant disorder that is characterized by nail and bone abnormalities and, frequently, renal disease. Well more than 500 cases have been described after the first description of the disorder by Little in 1837 (1). Nail hypoplasia or dysplasia and absent or hypoplastic patellae are essential features for the diagnosis. Other diagnostic signs are deformation or luxation of the head of the radius, resulting in impaired mobility of the elbow, and iliac horns, which are pathognomonic but reported to be present in only 70% of cases. Various other skeletal anomalies, such as pes equinovarus, dislocated hips, and contractures of major joints, have been described frequently in NPS but do not contribute to the diagnosis. Approximately 50% of affected individuals exhibit cloverleaf pigmentation of the inner margin of the iris. Its significance is unclear. One report described two families in which NPS cosegregated with open-angle glaucoma (2), suggesting that glaucoma may be another variable feature of the syndrome. The most serious component of NPS is the nephropathy, but this does not occur in all patients with the syndrome. In a retrospective study analyzing renal features of 123 observations in the literature, Meyrier et al. (3) discovered renal involvement in more than 60% of cases. In most cases, the nephropathy manifests only by chronic benign proteinuria. In approximately 15% of cases, however, the disease developed toward end-stage renal disease. It is unknown which factors are responsible for progression to renal insufficiency, and therefore renal prognosis is unpredictable. The light microscopy findings of renal biopsies in NPS are nonspecific. At the ultrastructural level, however, the glomeruli show a uniform and characteristic picture: irregular thickening of the glomerular basement membrane (GBM) with electron-lucent areas giving it a so-called “moth-eaten appearance.” Within the GBM and the mesangium, fibrillar collagen-like material is found, and finally there is fusion of epithelial foot processes. Remarkably, these ultrastructural changes have been found in all biopsied cases, independent of clinical involvement, and therefore do not seem to correlate with impaired renal function. In the late 1960s, the gene for NPS was assigned to the distal end of the long arm of chromosome 9 by the establishment of linkage of NPS to the ABO blood group locus and the adenylate kinase gene (4,5). It lasted a few decades, however, before the localization of the NPS gene could be significantly refined to a genetic interval of 1 cM in region 9q34.1 (6–9). Recently, Dreyer et al. (10) showed that NPS is caused by mutations in the LMX1B gene. The involvement of this gene in NPS was subsequently confirmed by others (11,12). Mutations in LMX1B were also found in families with NPS and glaucoma (11). LMX1B belongs to a family of highly related LIMhomeodomain transcription factors that are involved in pattern formation during development. These proteins contain two tandem LIM domains, which are cysteine-rich, zinc-binding domains that facilitate the interaction with other transcription factors: a homeodomain that has DNA-binding activity and a transcriptional activation domain (13). The identification of the Received November 10, 1999. Accepted February 3, 2000. Correspondence to Dr. Nine Knoers, Department of Human Genetics, University Hospital Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. Phone: 31-24-3613946; Fax: 31-24-3565026; E-mail: [email protected]