Iga Nephropathy, Susceptibility To, 3

A number sign (#) is used with this entry because of evidence that susceptibility to IgA nephropathy-3 (IGAN3) is caused by heterozygous mutation in the SPRY2 gene (602466) on chromosome 13q31. One such family has been reported.

For a phenotypic description and a discussion of genetic heterogeneity of IgA nephropathy, see IGAN1 (161950).

Clinical Features

Milillo et al. (2015) reported a 4-generation family of Sicilian descent with IgA nephropathy. Affected individuals had hypertension, proteinuria, and/or microhematuria. Renal biopsy, performed in 3 patients, showed IgA deposits. Two older patients had end-stage renal disease.

Inheritance

The transmission pattern of IGAN3 in the family reported by Milillo et al. (2015) was consistent with autosomal dominant inheritance.

Molecular Genetics

In affected members of a large Sicilian family with IGAN3, Milillo et al. (2015) identified a heterozygous missense mutation in the SPRY2 gene (R119W; 602466.0001). The mutation, which was found by exome sequencing, segregated with the disorder in family members over the age of 20 years; 3 family members under the age of 20 years did not have disease, although they were found to carry the mutation, suggesting age-dependent penetrance. Patient lymphoblastoid cells showed decreased amounts of SPRY2 mRNA, but normal protein levels resulting from increased stability of the mutant protein; there was no difference in the ratio between phosphorylated and nonphosphorylated forms compared to controls. Patient cells showed downregulation of the MAPK/ERK1/2 pathway. Cells from 2 unrelated patients with IgA nephropathy who did not have SPRY2 mutations also showed downregulation of the MAPK/ERK1/2 pathway, suggesting that it may be a common disease mechanism.