Clinical Investigation
Hereditary Renal Hypouricemia Type 1 and Autosomal Dominant Polycystic Kidney Disease

https://doi.org/10.1097/MAJ.0000000000000550Get rights and content

Abstract

Background

Renal hypouricemia (RHUC) is a heterogeneous inherited disorder characterized by impaired tubular uric acid (UA) transport with severe complications, such as acute kidney injury. Type 1 is caused by a mutation in the SLC22A12 gene (URAT1) and type 2 in the SLC2A9 gene (GLUT9). In this article, the authors present a coexpression functional characterization of variants responsible for RHUC type 1 in a Czech family with polycystic kidney disease (PKD).

Methods

The serum UA concentration in the proband was 1.1 mg/dL and was expressed as an increase in the fractional excretion of UA (43%). The URAT1 allelic variants were prepared and their urate uptake and subcellular localization were studied by Xenopus oocytes expression system. Linkage analysis using a panel of 4 CA-repeat flanking markers for chromosome 16 and a panel of 3 CA-repeat flanking markers for chromosome 4 was performed, which carry the PKD1 and PKD2 genes, respectively.

Results

Coexpression results showed that p.G366R and p.R477H suppressed urate transport by wild types. Colocalization studies showed an accumulation of URAT1 in the endoplasmic reticulum of the p.G366R variant and mainly retention of wild-type protein by variants p.G366R and p.R477H.

Conclusions

The findings suggest that not only loss-of-function mutation of URAT1 but also the dominant-negative effect cause RHUC through loss of UA absorption, partly due to protein misfolding caused by accumulation of URAT1 protein in the endoplasmic reticulum.

Section snippets

Subjects

All patients received information about the study, agreed to participate and signed an informed consent. All tests were performed in accordance with the standards of the institutional ethics committee that approved the project. A 40-year-old man (proband IV.1) was examined in the outpatient department, complaining of renal cysts: serum UA was 0.7 mg/dL, no medication; from 2012 medication TRITACE (ramipril), serum UA 0.9 mg/dL. Afterwards, the proband was referred to this department because of

Subjects

The serum UA concentration in the proband was 1.1 mg/dL and was expressed as an increase in the fractional excretion of UA (43%). The mother of the proband (70 years of age) has normal renal function with a serum of UA 3.5 mg/dL and a serum creatinine of 1.1 mg/dL. The mother's sister (66 years of age) has a UA serum level of 8.8 mg/dL, and the serum creatinine level was 1.9 mg/dL. The proband, his mother and sister did not have clinical symptoms of urolithiasis, nephrolithiasis, AKI or renal

DISCUSSION

Many genome-wide association studies have uncovered over 30 common sequence variants influencing serum UA concentrations in several genes, mostly in urate transporters SLC2A9, SLC22A12 and ABCG2.20., 21. Recent data suggest a new concept of renal UA transport—multimolecular complex “transportsome” that probably involves cooperation between multiple transporters.22 Further detailed studies concerning urate transporters and their interactions in rare hereditary disorder as is RHUC could clarify

CONCLUSIONS

In conclusion, the authors report the 1st family with extremely rare coexistence of renal hereditary disorders: RHUC type 1 and autosomal PKD.

Even with much research into renal UA transport, a complete understanding of the influence of serum UA concentrations and the molecular basis of the pathogenesis of RHUC has not yet been fully elucidated. Further investigation of the functional properties of SLC22A12 is needed to assess their potential research and clinical implications.

REFERENCES (22)

  • Y. Shima et al.

    Recurrent EIARF and PRES with severe renal hypouricemia by compound heterozygous SLC2A9 mutation

    Pediatrics

    (2011)
  • Cited by (17)

    • URAT1 and GLUT9 mutations in Spanish patients with renal hypouricemia

      2018, Clinica Chimica Acta
      Citation Excerpt :

      Coincidentally, one of the adult patients with CKD, patient 1, also had ADPKD. Stiburkova and col. [42] recently described a similar case. Our genetic analysis results showed SLC22A12 mutations p.T467M and/or p.L415_G417del in all the Roma patients; missense mutation p.T467M was detected in seven patients of five families (four homozygous, two heterozygous and one compound heterozygous), while mutation p.L415_G417del was found in two patients (one heterozygous and one compound heterozygous) (Table 1).

    • Hereditary renal hypouricaemia type 1 and 2 in three Spanish children. Review of published paediatric cases

      2019, Nefrologia
      Citation Excerpt :

      Hereditary renal hypouricaemia (HRH) is a rare and underdiagnosed genetic disorder, and is included in the group of rare diseases (ORPHA 94088). It is caused by an isolated defect in the renal transport of uric acid at the renal tubular level, either due to decreased reabsorption and/or increased secretion.1,2 In children over 1 year old and in adults, it must be suspected in the presence of persistent serum uric acid (UA) level of less than 2 mg/dl (119 μmol/l), with fractional excretion of UA (FEUA) above 10% (normal 7.25 ± 2.98%).3–5

    View all citing articles on Scopus

    The authors have no other conflicts of interest to disclose.

    Supported by grants from the Czech Republic Ministry of Education, Youth and Sports (LH13245) and by institutional support from a program at Charles University in Prague (PRVOUK—P25/LF1/2, P24/LF1/3).

    View full text