title: A novel LMX1B mutation in a family with end-stage renal disease of 'unknown cause'.
abstract: End-stage renal disease (ESRD) presenting in a familial autosomal dominant pattern points to an underlying monogenic cause. Nail-patella syndrome (NPS) is an autosomal dominant disorder that may lead to ESRD caused by mutations in the transcription factor LMX1B. Renal-limited forms of this disease, termed nail-patella-like renal disease (NPLRD), and LMX1B nephropathy have recently been described. We report a large family, from the North East of England, with seven affected members with varying phenotypes of renal disease, ranging from ESRD at 28 years of age to microscopic haematuria and proteinuria and relatively preserved renal function. In this family, there were no extra-renal manifestations to suggest NPS. Genome-wide linkage studies and inheritance by descent (IBD) suggested disease loci on Chromosome 1 and 9. Whole exome sequencing (WES) analysis identified a novel sequence variant (p.R249Q) in the LMX1B gene in each of the three samples submitted, which was confirmed using Sanger sequencing. The variant segregated with the disease in all affected individuals. In silico modelling revealed that R249 is putatively located in close proximity to the DNA phosphoskeleton, supporting a role for this residue in the interaction between the LMX1B homeodomain and its target DNA. WES and analysis of potential target genes, including CD2AP, NPHS2, COL4A3, COL4A4 and COL4A5, did not reveal any co-inherited pathogenic variants. In conclusion, we confirm a novel LMX1B mutation in a large family with an autosomal dominant pattern of nephropathy. This report confirms that LMX1B mutations may cause a glomerulopathy without extra-renal manifestations. A molecular genetic diagnosis of LMX1B nephropathy thus provides a definitive diagnosis, prevents the need for renal biopsies and allows at risk family members to be screened.
authors.affiliation: Institute of Genetic Medicine , International Centre for Life, Newcastle University , Newcastle upon Tyne , UK ; Institute for Cell and Molecular Biosciences, Faculty of Medical Sciences, Framlington Place , Newcastle University , Newcastle upon Tyne , UK.
authors.forename: Noel
authors.initials: N
authors.lastname: Edwards
authors.affiliation: Institute of Genetic Medicine , International Centre for Life, Newcastle University , Newcastle upon Tyne , UK ; Institute for Cell and Molecular Biosciences, Faculty of Medical Sciences, Framlington Place , Newcastle University , Newcastle upon Tyne , UK.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Rice
authors.affiliation: Royal Victoria Infirmary , Newcastle upon Tyne NHS Hospitals Foundation Trust , Newcastle upon Tyne , UK.
authors.forename: Shreya
authors.initials: S
authors.lastname: Raman
authors.affiliation: Institute of Genetic Medicine , International Centre for Life, Newcastle University , Newcastle upon Tyne , UK.
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Hynes
authors.affiliation: Institute of Genetic Medicine , International Centre for Life, Newcastle University , Newcastle upon Tyne , UK.
authors.forename: Shalabh
authors.initials: S
authors.lastname: Srivastava
authors.affiliation: Renal Unit , Sunderland Royal Infirmary , Sunderland , UK.
authors.forename: Iain
authors.initials: I
authors.lastname: Moore
authors.affiliation: Institute of Genetic Medicine , International Centre for Life, Newcastle University , Newcastle upon Tyne , UK.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Al-Hamed
authors.affiliation: Institute of Genetic Medicine , International Centre for Life, Newcastle University , Newcastle upon Tyne , UK.
authors.forename: Yaobo
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Institute of Genetic Medicine , International Centre for Life, Newcastle University , Newcastle upon Tyne , UK.
authors.forename: Mauro
authors.initials: M
authors.lastname: Santibanez-Koref
authors.affiliation: Institute for Cell and Molecular Biosciences, Faculty of Medical Sciences, Framlington Place , Newcastle University , Newcastle upon Tyne , UK.
authors.forename: David T
authors.initials: DT
authors.lastname: Thwaites
authors.affiliation: UCL Centre for Nephrology , Royal Free Hospital , London , UK.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Gale
authors.affiliation: Institute of Genetic Medicine , International Centre for Life, Newcastle University , Newcastle upon Tyne , UK.
authors.forename: John A
authors.initials: JA
authors.lastname: Sayer
keywords: LMX1B; end-stage renal disease; podocytopathy; proteinuria; transcription factor