Identification of a Locus on the X Chromosome Linked to Familial Membranous Nephropathy

Research output: Contribution to journalArticlepeer-review

  • External authors:
  • Mallory L Downie
  • Sanjana Gupta
  • Mehmet C Tekman
  • Chris Cheshire
  • Steven Arora
  • Christoph Licht
  • Lisa A Robinson
  • Marina Munoz
  • Alvaro Madrid Aris
  • Ibrahim Al Attrach
  • Daniel P Gale
  • Horia Stanescu
  • Detlef Bockenhauer
  • Robert Kleta

Abstract

Introduction: Membranous nephropathy (MN) is the most common cause of nephrotic syndrome (NS) in adults and is a leading cause of end-stage renal disease due to glomerulonephritis. Primary MN has a strong male predominance, accounting for approximately 65% of cases; yet, currently associated genetic loci are all located on autosomes. Previous reports of familial MN have suggested the existence of a potential X-linked susceptibility locus. Identification of such risk locus may provide clues to the etiology of MN.

Methods: We identified 3 families with 8 members affected by primary MN. Genotyping was performed using single-nucleotide polymorphism microarrays, and serum was sent for anti-phospholipase A2 receptor (PLA2R) antibody testing. All affected members were male and connected through the maternal line, consistent with X-linked inheritance. Genome-wide multipoint parametric linkage analysis using a model of X-linked recessive inheritance was conducted, and genetic risk scores (GRSs) based on known MN-associated variants were determined.

Results: Anti-PLA2R testing was negative in all affected family members. Linkage analysis revealed a significant logarithm of the odds score (3.260) on the short arm of the X chromosome at a locus of approximately 11 megabases (Mb). Haplotype reconstruction further uncovered a shared haplotype spanning 2 Mb present in all affected individuals from the 3 families. GRSs in familial MN were significantly lower than in anti-PLA2R-associated MN and were not different from controls.

Conclusions: Our study identifies linkage of familial membranous nephropathy to chromosome Xp11.3-11.22. Family members affected with MN have a significantly lower GRS than individuals with anti-PLA2R-associated MN, suggesting that X-linked familial MN represents a separate etiologic entity.

Bibliographical metadata

Original languageEnglish
Pages (from-to)1669-1676
Number of pages8
JournalKidney International Reports
Volume6
Issue number6
Early online date3 Mar 2021
DOIs
Publication statusPublished - Jun 2021