Angiomotin mutation causes glomerulopathy and renal cysts by upregulating hepatocyte nuclear factor transcriptional activity

Dear editor, We identified angiomotin (AMOT) as a novel candidate gene for X-linked recessive nephropathy associated with glomerular disease, tubulopathy and progressive kidney cystic disease. Transgenic rats carrying this mutation recapitulated the human phenotype to some extent. Orthogonal methods implicate the hepatocyte nuclear factor (Hnf) family of transcription factors, particularly Hnf4α and Hnf1β, in the development of Amot mutation-induced nephropathy. Monogenic causes involving more than 50 genes have been identified in 25%–30% of young patients with steroidresistant nephrotic syndrome (SRNS).1,2 We report a family with X-linked recessive early-onset SRNS and Fanconi syndrome (Figure 1A–D). Exome sequencing identified NM_001113490.1:c.148A>G (p. S50G) variant in exon 1 of AMOT, which encodesAMOT. This variant causes the substitution of serine to glycine at the 50th position of AMOTP130 (Figures 1E,F and S1). To study the effects of this mutation in rats, we used the CRISPR/Cas9 system to substitute both serine and threonine residues at positions 49–50 with proline and glycine (termed ‘PG’ rat) or proline and serine (termed ‘PS’ rat), respectively (Figure S2). PG rats developed higher body weights and albuminuria (Figure 1G,H). At 6 months old, PG rats developed focal segmental glomerulosclerosis, tubular dilatation, tubulointerstitial inflammation and fibrosis (Figure 1J–L). Systematic scoring of the light microscopic changes revealed no kidney abnormalities in wild type (WT) and PS rats, while the PG rats had minimal to moderate changes (Figure 1M). We then examined the ultrastructural changes at 3 months old.WhileWT rats had normal morphology, the podocytes in PG rats showed extensive foot process effacement and detachment, revealing areas with nude glomerular basement membranes (Figure 1N). At 21 days old, macroscopic cysts were also