title: LMX1B mutations cause hereditary FSGS without extrarenal involvement.
abstract: LMX1B encodes a homeodomain-containing transcription factor that is essential during development. Mutations in LMX1B cause nail-patella syndrome, characterized by dysplasia of the patellae, nails, and elbows and FSGS with specific ultrastructural lesions of the glomerular basement membrane (GBM). By linkage analysis and exome sequencing, we unexpectedly identified an LMX1B mutation segregating with disease in a pedigree of five patients with autosomal dominant FSGS but without either extrarenal features or ultrastructural abnormalities of the GBM suggestive of nail-patella-like renal disease. Subsequently, we screened 73 additional unrelated families with FSGS and found mutations involving the same amino acid (R246) in 2 families. An LMX1B in silico homology model suggested that the mutated residue plays an important role in strengthening the interaction between the LMX1B homeodomain and DNA; both identified mutations would be expected to diminish such interactions. In summary, these results suggest that isolated FSGS could result from mutations in genes that are also involved in syndromic forms of FSGS. This highlights the need to include these genes in all diagnostic approaches to FSGS that involve next-generation sequencing.
authors.affiliation: Inserm U983, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: Olivia
authors.initials: O
authors.lastname: Boyer
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Woerner
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Oakeley
authors.forename: Bolan
authors.initials: B
authors.lastname: Linghu
authors.forename: Olivier
authors.initials: O
authors.lastname: Gribouval
authors.forename: Marie-Josèphe
authors.initials: MJ
authors.lastname: Tête
authors.forename: José S
authors.initials: JS
authors.lastname: Duca
authors.forename: Lloyd
authors.initials: L
authors.lastname: Klickstein
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Damask
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Szustakowski
authors.forename: Françoise
authors.initials: F
authors.lastname: Heibel
authors.forename: Marie
authors.initials: M
authors.lastname: Matignon
authors.forename: Véronique
authors.initials: V
authors.lastname: Baudouin
authors.forename: François
authors.initials: F
authors.lastname: Chantrel
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Champigneulle
authors.forename: Laurent
authors.initials: L
authors.lastname: Martin
authors.forename: Patrick
authors.initials: P
authors.lastname: Nitschké
authors.forename: Marie-Claire
authors.initials: MC
authors.lastname: Gubler
authors.forename: Keith J
authors.initials: KJ
authors.lastname: Johnson
authors.forename: Salah-Dine
authors.initials: SD
authors.lastname: Chibout
authors.forename: Corinne
authors.initials: C
authors.lastname: Antignac
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D005260:Female; D005799:Genes, Dominant; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics*; D006801:Humans; D060850:LIM-Homeodomain Proteins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009261:Nail-Patella Syndrome / Q000235:genetics*; D010375:Pedigree; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics*; D055815:Young Adult
chemical_list: C112149:LIM homeobox transcription factor 1 beta; D060850:LIM-Homeodomain Proteins; D014157:Transcription Factors