title: 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 of FSGS patients develop chronic kidney failure within 10 years, ultimately requiring dialysis or renal transplantation. There are currently several genes known to 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 two mutated 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 this mutation in these co-morbid disorders. Further studies are now required to determine the functional consequence of these novel mutations to development of FSGS and heart block in this pedigree and to determine whether these mutations have implications for more common forms of these diseases in the general population.
authors.affiliation: Institute of Genetics and Biophysics Adriano Buzzati-Traverso, National Research Council of Italy, Naples, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Esposito
authors.forename: Rod A
authors.initials: RA
authors.lastname: Lea
authors.forename: Bridget H
authors.initials: BH
authors.lastname: Maher
authors.forename: Dianne
authors.initials: D
authors.lastname: Moses
authors.forename: Hannah C
authors.initials: HC
authors.lastname: Cox
authors.forename: Sara
authors.initials: S
authors.lastname: Magliocca
authors.forename: Andrea
authors.initials: A
authors.lastname: Angius
authors.forename: Dale R
authors.initials: DR
authors.lastname: Nyholt
authors.forename: Thomas
authors.initials: T
authors.lastname: Titus
authors.forename: Troy
authors.initials: T
authors.lastname: Kay
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Gray
authors.forename: Maria P
authors.initials: MP
authors.lastname: Rastaldi
authors.forename: Alan
authors.initials: A
authors.lastname: Parnham
authors.forename: Fernando
authors.initials: F
authors.lastname: Gianfrancesco
authors.forename: Lyn R
authors.initials: LR
authors.lastname: Griffiths
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001315:Australia; D002648:Child; D002675:Child, Preschool; D059472:Exome; D005260:Female; D050172:Genes, X-Linked; D040181:Genetic Diseases, X-Linked / Q000235:genetics*; D008040:Genetic Linkage; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics*; D057809:HEK293 Cells; D006327:Heart Block / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009154:Mutation; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics; D029543:Nucleocytoplasmic Transport Proteins / Q000235:genetics*; D009928:Organ Specificity; D010375:Pedigree; D016601:RNA-Binding Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA; D055815:Young Adult
chemical_list: C443839:NXF5 protein, human; D029543:Nucleocytoplasmic Transport Proteins; D016601:RNA-Binding Proteins; C583889:ALG13 protein, human; D017351:N-Acetylglucosaminyltransferases