Edwards, Noel;
Rice, Sarah J;
Raman, Shreya;
Hynes, Ann Marie;
Srivastava, Shalabh;
Moore, Iain;
Al-Hamed, Mohamed;
... Sayer, John A; + view all
(2015)
A novel LMX1B mutation in a family with end-stage renal disease of 'unknown cause'.
Clinical Kidney Journal
, 8
(1)
pp. 113-119.
10.1093/ckj/sfu129.
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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.
| Type: | Article |
|---|---|
| Title: | A novel LMX1B mutation in a family with end-stage renal disease of 'unknown cause' |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1093/ckj/sfu129 |
| Publisher version: | http://dx.doi.org/10.1093/ckj/sfu129 |
| Language: | English |
| Additional information: | © The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA.This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Urology & Nephrology, end-stage renal disease, LMX1B, podocytopathy, proteinuria, transcription factor |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Renal Medicine |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10196192 |
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