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

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, Paul E Brenchley, Daniel P Gale, Horia Stanescu, Detlef Bockenhauer, Robert Kleta

Research output: Contribution to journalArticlepeer-review


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.

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


  • LOD score
  • X-linked
  • genetic risk score
  • glomerulonephritis
  • linkage analysis
  • membranous nephropathy


Dive into the research topics of 'Identification of a Locus on the X Chromosome Linked to Familial Membranous Nephropathy'. Together they form a unique fingerprint.

Cite this