LMX1B mutations as an unexpected cause of hereditary focal segmental glomerulosclerosis without extra-renal involvement

The recent identification of podocyte gene mutations in familial forms of focal segmental glomerulosclerosis (FSGS), some of which associated with various extra-renal features, has helped decipher the glomerular filtration barrier pathophysiology. LMX1B mutations lead to Nail-Patella syndrome, characterized by dysplasia of the patellae, nails and elbows, and FSGS with specific glomerular basement membrane ultrastructural lesions. By linkage analysis and exome sequencing, we unexpectedly identified a novel LMX1B mutation segregating with the disease in a pedigree of 5 patients with autosomal dominant FSGS but no glomerular basement membrane anomaly suggestive of Nail-Patella-like renal disease by electron microscopy, and no extra-renal features. Subsequently, we screened 73 additional unrelated families with FSGS and found mutations of the same residue in 2 families. LMX1B encodes a homeodomain-containing transcription factor that is essential during development. A LMX1B in silico homology model suggests the mutated residue plays an important role in strengthening the interaction between the LMX1B homeodomain and DNA molecule. Both mutations are expected to diminish such interactions. Our data demonstrate that isolated FSGS could be due to mutations in genes also involved in syndromic forms and highlights the need to include these genes in all next-generation sequencing diagnosis approaches in FSGS.