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

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.

Keywords: LOD score; X-linked; genetic risk score; glomerulonephritis; linkage analysis; membranous nephropathy.

Graphical abstract

Figure 1

Pedigrees and haplotypes of families 1, 2, and 3 with familial membranous nephropathy. Squares indicate males and circles indicate females. A black symbol indicates that the individual is affected, a white symbol indicates the individual is unaffected, and a grey symbol indicates that the individual’s affectation status is unknown. Asterisks indicate individuals who were genotyped and included in the study. Red boxes indicate the shared haplotype (rs12843640-rs5991828). Pedigree analysis in all 3 families showed a pattern consistent with X-linked recessive inheritance (i.e., only males are affected and inheritance is via the maternal line with no male-to-male transmission).

Figure 2

Box and whisker plot shows genetic risk scores (GRSs) in familial membranous nephropathy (MN). Median values (line inside the box) for each group with upper and lower quartiles (top and bottom) are represented by boxes, with whiskers delineating variability outside quartiles. Outliers are plotted as individual point beyond whisker limits. Asterisks indicate P < 0.05 using the χ² test with the Bonferroni correction.

Figure 3

Multipoint parametric linkage analysis on chromosome X for families 1, 2, and 3. The y axis shows the logarithm of the odds (LOD) score, and the x axis gives the genomic position in megabases (Mb). Note significant linkage of 3.260 in the region of 43 to 54 Mb (reference genome: GRCh37). The red box indicates the area of shared identical haplotype in all 3 families (51–53 Mb).