All the mutations affect the homeodomain of the LMX1B protein and could cause the Nail-Patella syndrome through a loss of function as well as a dominant negative effect.
Taken together, our studies suggest a developmental etiology for glaucoma in NPS patients and highlight lmx1b as an essential regulator of anterior segment morphogenesis and patterning. genesis 26:15-25, 2000.
Variants in the LMX1B gene cause nail-patella syndrome, a rare autosomal dominant disorder characterized by dysplasia of nails, patella and elbow abnormalities, iliac "horns," and glaucoma.
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.
Nail-patella syndrome (NPS) is rare genetic disorder with autosomal mode of inheritance resulting from mutations in the LMX1B gene mapped on the long arm of chromosome 9 (9q34), encoding transcription factor, also named LMX1B.
Molecular studies of Lmx1b, combined with genetic and immunohistochemical investigation of different alpha chains of type IV collagen in the Lmx1b null mice kidney, a mouse model for NPS, have provided evidence that Lmx1b is involved in the pathogenesis of NPS glomerulopathy.
In the present study, we analyzed the LMX1B gene in three Japanese patients with NPS and identified two novel mutations, 6 nucleotide deletion (Delta246N 247Q) and V242L.
This is the first report that a mutation in the LMX1B gene causes NPS in a Chinese population, which will expand the spectrum of mutations in the LMX1B gene and provide insight into the underlining pathology of NPS.
These findings support the hypothesis that NPS results from a 50% reduction in LMX1B function via a reduction in synthesis, disruption of secondary structure, or failure to bind DNA.
Here, we present exome sequencing and analysis of four generations of a family with a dominantly inherited Nail-Patella-like disorder (nail dysplasia with some features of Nail-Patella syndrome) who tested negative forLMX1B mutation.
The molecular interaction between LMX1B and PAX2 has been already reported in vitro and this finding suggest that the worst renal NPS phenotype of our patient could be due to the defective expression of these two genes during nephrogenesis.
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.
These findings help to explain the high degree of variability in the NPS phenotype, and suggest that the skeletal defects in NPS are a result of the diminished dorsoventral patterning activity of LMX1B protein during limb development.
This suggests that the locus 9q33-9q34 can be excluded for GPS and that the presented case is unique in its combination of GPS and NPS features caused by a microdeletion associated with loss of function of LMX1B and NR5A1.
NPS is inherited as an autosomal dominant trait and caused by heterozygous loss of function mutations in LMX1B, a member of the LIM homeodomain protein family.
Previous studies have identified mutations in the RSPO4 and LMX1B components of the Wnt pathway in patients with the hypoplastic nail disorders anonychia and nail-patella syndrome, respectively.