Discovery of a novel dominant mutation in the REN gene after forty years of renal disease: a case report

Abstract

BackgroundHeterozygous mutations in the gene encoding renin (REN) cause autosomal dominant tubulointerstitial kidney disease (ADTKD), early-onset anaemia and hyperuricaemia; only four different mutations have been described in the published literature to date. We report a novel dominant REN mutation discovered in an individual after forty years of renal disease.Case presentationA 57 year old Caucasian woman with chronic kidney disease stage five was reviewed in a regional joint renal genetics clinic. She had initially been diagnosed with chronic pyelonephritis in adolescence, around the same time that she was investigated for anaemia out of keeping with her degree of renal impairment. Hyperuricaemia was identified in her twenties following an episode of gout. A diagnosis of ADTKD was not made until the age of 37 years, when her mother was also found to have kidney disease and commenced haemodialysis. The patient’s renal function continued to slowly deteriorate and, twenty years later, her sister was worked up as a potential donor for kidney transplantation. Revisiting the maternal family history during the transplant work up prompted a referral to clinical genetics and urgent REN genetic testing was requested for the patient, leading to discovery of a heterozygous mutation in the REN gene: c.49 T > C, p.(Trp17Arg). This variant was not identified in her otherwise healthy sister, allowing pre-emptive live renal transplantation to take place shortly afterwards.ConclusionsIn an era where genetic testing is becoming much more readily available, this case highlights the importance of considering a genetic aetiology in all patients with long-standing renal disease and a relevant family history. Establishing a genetic diagnosis of ADTKD-REN in this individual with chronic anaemia, hyperuricaemia and slowly progressive renal impairment helped to identify a suitable live kidney donor and allowed successful pre-emptive transplantation to take place.

Autosomal Dominant Tubulointerstitial Kidney Disease with Adult Onset due to a Novel Renin Mutation Mapping in the Mature Protein

“…In this study, we report a new ADTKD family in which we identified a novel renin mutation mapping in exon 10 of the gene, hence outside of the region where all previously identified mutations have been reported (exon 1) 4–7 . Affected family members presented adult-onset chronic tubulointerstitial kidney disease and hyperuricemia and gout.…”

“…The large majority of ADTKD patients are carriers of mutations in UMOD or MUC1 genes 2,3 . ADTKD- REN (previously known as Familial Juvenile Hyperuricemic Nephropathy type 2 [FJHN2], MIM# 613092) represents a very rare condition, as so far 6 families have been described worldwide 4–7 . Although most of ADTKD characteristics including clinical, laboratory and histological findings are rather nonspecific, some features appear to be relatively distinctive for individual genetic forms.…”

“…Instead, dominant mutations reported to date in ADTKD- REN families are all non-truncating, missense changes (W10R, L16R, W17R and C20R) or an in-frame deletion (L16del) mapping in the first exon of the gene and affecting residues within the protein leader peptide 4–7 . To date only three mutations (L16del, L16R, C20R) have been studied in transfected cells 4–6 .…”

An international cohort study of autosomal dominant tubulointerstitial kidney disease due to mutations identifies distinct clinical subtypes

“…[2][3][4][5] ADTKD due to mutations in the REN gene encoding renin (ADTKD-REN) is one of the least common forms of ADTKD, 5 with only 8 families and 28 individuals reported before 2020. [5][6][7][8][9][10][11] Renin is a hormone primarily produced in the kidney that is requisite for tubulogenesis 12 and embryonic kidney formation. 13 The renin-angiotensin system is a key modulator of blood pressure 14 and CKD progression.…”

“…17 In ADTKD-REN, heterozygous REN mutations lead to decreased synthesis of prorenin and renin, resulting in mild hyperkalemia, anemia, hyperuricemia, and a predisposition to the development of acute kidney injury. 5 REN mutations have been reported in the segment of the REN gene encoding the signal peptide [5][6][7][8] and the mature renin protein. 9,10 Mutations in the prosegment-a segment of the gene after the signal peptide that assists in protein folding-have not been reported.…”