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.

Clinical and histological findings of autosomal dominant renal‐limited disease with LMX1B mutation

“…). In previous reports, several patterns of pathology (such as MCD, FSGS and mesangial proliferative glomerulonephritis) were observed in patients manifesting renal‐limited phenotypes of LMX1B mutation . In this manner, light microscopy findings for this disease varied by disease duration.…”

Dysregulation of WTI (−KTS) is Associated with the Kidney-Specific Effects of the LMX1B R246Q Mutation

“…We conducted an extensive literature search to identify studies describing the renal limited phenotype associated with LMX1B mutations6789. We identified four studies reporting three mutations in the LMX1B DNA binding homeodomains, these studies reported on six families with LMX1B mutations.…”

“…It has previously been observed that patients with NPS caused by a LMX1B mutation located in the homeodomain showed significantly more frequent and more severe renal involvement compared with patients with mutations outside of this domain3. More recently, a renal specific missense mutation (R246Q) in the homeobox domain of LMX1B (LMX1B R246Q ) has been reported by different groups in France, United Kingdom and Japan6789. In each of these families, all of the affected individuals presented with glomerular pathologies without skeletal or other extra-renal manifestations.…”

The expanding phenotypic spectra of kidney diseases: insights from genetic studies

“…NPS and glomerulopathy (AD) [69][70][71]144 Mutations associated with an isolated glomerulopathy are located in the homeodomain of LMX1B, possibly disrupting the interaction between LMX1B and (podocyte specific) DNA targets [69][70][71] …”

“…Finally, different inheritance patterns or mutation types in genes involved in syndromic kidney disease can cause an isolated kidney phenotype at the mild end of the phenotypic spectrum. Examples are mutations in LMX1B, which are associated with nail-patella syndrome (OMIM 161200) but can also cause an isolated glomerulopathy [69][70][71] , and mutations in OCRL1, which cause Lowe oculocerebrorenal syndrome (OMIM 309000), but also cause Dent disease 2 (OMIM 300555) 72 . Another example is provided by FRAS1 and FREM2, in which biallelic truncating mutations cause Fraser syndrome (OMIM 219000).…”