Unique X-linked familial FSGS with co-segregating heart block disorder is associated with a mutation in the NXF5 gene

Abstract

Focal segmental glomerulosclerosis (FSGS) is the consequence of a disease process that attacks the kidney's filtering system, causing serious scarring. More than half ofFSGSpatients develop chronic kidney failure within 10 years, ultimately requiringdialysis or renal transplantation. There are currently several genesknownto cause the hereditary forms of FSGS (ACTN4, TRPC6, CD2AP, INF2, MYO1E and NPHS2). This study involves a large, unique, multigenerational Australian pedigree in which FSGS co-segregates with progressive heart block with apparent X-linked recessive inheritance. Through a classical combined approach of linkage and haplotype analysis, we identified a 21.19 cM interval implicated on the X chromosome. We then used a whole exome sequencing approach to identify twomutated genes, NXF5 and ALG13,which are located within this linkage interval. The two mutations NXF5-R113W and ALG13-T141L segregated perfectly with the disease phenotype in the pedigree and were not found in a large healthy control cohort. Analysis using bioinformatics tools predicted the R113W mutation in the NXF5 gene to be deleterious and cellular studies support a role in the stability and localization of the protein suggesting a causative role of thismutation in these co-morbid disorders. Further studies arenowrequired to determine the functionalconsequenceof thesenovel mutations todevelopmentofFSGSand heart block in this pedigreeandto determinewhether these mutationshaveimplicationsformorecommonforms of these diseases in the general population. © The Author 2013. Published by Oxford University Press. All rights reserved.