Skip to main content
SpringerLink
Log in

Clinical and genetic characterization of children with cubilin variants

  • Brief Report
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript

Abstract

Background

Cubilin is one of the receptor proteins responsible for reabsorption of albumin in proximal tubules and is encoded by the CUBN gene. We aimed to evaluate clinical and genetic characterization of six patients with proteinuria who had CUBN mutations.

Methods

Patients’ characteristics, serum creatinine, albumin, vitamin B12 levels, urine analysis, spot urine protein/creatinine, microalbumin/creatinine, beta-2 microglobulin/creatinine ratios, estimated glomerular filtration rates (eGFR), treatments, kidney biopsies, and genetic analyses were evaluated.

Results

Six patients (2 female, 4 male) with an incidental finding of proteinuria were evaluated. Mean admission age and follow-up time were 7.3 ± 2.9 and 6.5 ± 5.6 years, respectively. Serum albumin, creatinine, and eGFR were normal; urine analysis revealed no hematuria, and C3, C4, ANA, and anti-DNA were negative; kidney ultrasonography was normal for all patients. Urine protein/creatinine was 0.9 ± 0.3 mg/mg, and microalbumin was high in all patients. Serum vitamin B12 was low in two patients and normal in four. Kidney biopsy was performed in four patients, three demonstrated normal light microscopy, and there was one focal segmental glomerulosclerosis (FSGS). Genetic tests revealed four homozygous and two compound heterozygous mutations in the C-terminal part of cubilin. All patients had normal eGFR and still had non-nephrotic range proteinuria at last visit.

Conclusions

CUBN gene mutations should be considered in patients with isolated non-nephrotic range proteinuria and normal kidney function. Diagnosing these patients, who are thought to have a better prognosis, is important in terms of avoiding unnecessary treatment and predicting prognosis. CUBN gene mutations may also present as FSGS which extends the spectrum of renal manifestation of these patients.

Graphical abstract

A higher resolution version of the Graphical abstract is available as Supplementary information

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

References

  1. Hemmelgarn BR, Manns BJ, Lloyd A, James MT, Klarenbach S, Quinn RR, Wiebe N, Tonelli M; Alberta Kidney Disease Network (2010) Relation between kidney function, proteinuria, and adverse outcomes. JAMA 303:423–429. https://doi.org/10.1001/jama.2010.39

  2. Amsellem S, Gburek J, Hamard G, Nielsen R, Willnow TE, Devuyst O, Nexo E, Verroust PJ, Christensen EI, Kozyraki R (2010) Cubilin is essential for albumin reabsorption in the renal proximal tubule. J Am Soc Nephrol 21:1859–1867. https://doi.org/10.1681/ASN.2010050492

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Birn H, Fyfe JC, Jacobsen C, Mounier F, Verroust PJ, Orskov H, Willnow TE, Moestrup SK, Christensen EI (2000) Cubilin is an albumin binding protein important for renal tubular albumin reabsorption. J Clin Invest 105:1353–1361. https://doi.org/10.1172/JCI8862

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Aminoff M, Carter JE, Chadwick RB, Johnson C, Grasbeck R, Abdelaal MA, Broch H, Jenner LB, Verroust PJ, Moestrup SK, de la Chapelle A, Krahe R (1999) Mutations in CUBN, encoding the intrinsic factor-vitamin B12 receptor, cubilin, cause hereditary megaloblastic anaemia 1. Nat Genet 21:309–313. https://doi.org/10.1038/6831

    Article  CAS  PubMed  Google Scholar 

  5. Ercan Z, Demir ME, Ulas T, Ingec M, Horoz M (2013) A long-term follow-up of an Imerslund Grasbeck syndrome patient with proteinuria. Nefrologia 33:147–148. https://doi.org/10.3265/Nefrologia.pre2012.Aug.11661

    Article  PubMed  Google Scholar 

  6. O’Toole JF, Sedor JR (2011) Are cubilin (CUBN) variants at the heart of urinary albumin excretion? J Am Soc Nephrol 22:404–406. https://doi.org/10.1681/ASN.2011010097

    Article  PubMed  Google Scholar 

  7. Bedin M, Boyer O, Servais A, Li Y, Villoing-Gaudé L, Tête MJ, Cambier A, Hogan J, Baudouin V, Krid S, Bensman A, Lammens F, Louillet F, Ranchin B, Vigneau C, Bouteau I, Isnard-Bagnis C, Mache CJ, Schäfer T, Pape L, Gödel M, Huber TB, Benz M, Klaus G, Hansen M, Latta K, Gribouval O, Morinière V, Tournant C, Grohmann M, Kuhn E, Wagner T, Bole-Feysot C, Jabot-Hanin F, Nitschké P, Ahluwalia TS, Köttgen A, Andersen CBF, Bergmann C, Antignac C, Simons M  (2020) Human C-terminal CUBN variants associate with chronic proteinuria and normal renal function. J Clin Invest 130:335–344. https://doi.org/10.1172/JCI129937

    Article  CAS  PubMed  Google Scholar 

  8. Schwartz GJ, Munoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, Furth SL (2009) New equations to estimate GFR in children with CKD. J Am Soc Nephrol 20:629–637. https://doi.org/10.1681/ASN.2008030287

    Article  PubMed  PubMed Central  Google Scholar 

  9. Boger CA, Chen MH, Tin A, Olden M, Köttgen A, de Boer IH, Fuchsberger C, O’Seaghdha CM, Pattaro C, Teumer A, Liu CT, Glazer NL, Li M, O’Connell JR, Tanaka T, Peralta CA, Kutalik Z, Luan J, Zhao JH, Hwang SJ, Akylbekova E, Kramer H, van der Harst P, Smith AV, Lohman K, de Andrade M, Hayward C, Kollerits B, Tönjes A, Aspelund T, Ingelsson E, Eiriksdottir G, Launer LJ, Harris TB, Shuldiner AR, Mitchell BD, Arking DE, Franceschini N, Boerwinkle E, Egan J, Hernandez D, Reilly M, Townsend RR, Lumley T, Siscovick DS, Psaty BM, Kestenbaum B, Haritunians T, Bergmann S, Vollenweider P, Waeber G, Mooser V, Waterworth D, Johnson AD, Florez JC, Meigs JB, Lu X, Turner ST, Atkinson EJ, Leak TS, Aasarød K, Skorpen F, Syvänen AC, Illig T, Baumert J, Koenig W, Krämer BK, Devuyst O, Mychaleckyj JC, Minelli C, Bakker SJ, Kedenko L, Paulweber B, Coassin S, Endlich K, Kroemer HK, Biffar R, Stracke S, Völzke H, Stumvoll M, Mägi R, Campbell H, Vitart V, Hastie ND, Gudnason V, Kardia SL, Liu Y, Polasek O, Curhan G, Kronenberg F, Prokopenko I, Rudan I, Arnlöv J, Hallan S, Navis G; CKDGen Consortium, Parsa A, Ferrucci L, Coresh J, Shlipak MG, Bull SB, Paterson NJ, Wichmann HE, Wareham NJ, Loos RJ, Rotter JI, Pramstaller PP, Cupples LA, Beckmann JS, Yang Q, Heid IM, Rettig R, Dreisbach AW, Bochud M, Fox CS, Kao WH (2011) CUBN is a gene locus for albuminuria. J Am Soc Nephrol 22:555–570. https://doi.org/10.1681/ASN.2010060598

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Prabakaran T, Christensen EI, Nielsen R, Verroust PJ (2012) Cubilin is expressed in rat and human glomerular podocytes. Nephrol Dial Transplant 27:3156–3159. https://doi.org/10.1093/ndt/gfr794

    Article  CAS  PubMed  Google Scholar 

  11. Gianesello L, Priante G, Ceol M, Radu CM, Saleem MA, Simioni P, Terrin L, Anglani F, Del Prete D (2017) Albumin uptake in human podocytes: a possible role for the cubilin-amnionless (CUBAM) complex. Sci Rep 7:13705. https://doi.org/10.1038/s41598-017-13789-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ovunc B, Otto EA, Vega-Warner V, Saisawat P, Ashraf S, Ramaswami G, Fathy HM, Schoeb D, Chernin G, Lyons RH, Yilmaz E, Hildebrandt F (2011) Exome sequencing reveals cubilin mutation as a single-gene cause of proteinuria. J Am Soc Nephrol 22:1815–1820. https://doi.org/10.1681/ASN.2011040337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Jayasinghe K, White SM, Kerr PG, MacGregor D, Stark Z, Wilkins E, Simons C, Mallett A, Quinlan C (2019) Isolated proteinuria due to CUBN homozygous mutation - challenging the investigative paradigm. BMC Nephrol 20:330. https://doi.org/10.1186/s12882-019-1474-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Domingo-Gallego A, Pybus M, Madariaga L, Piñero-Fernández JA, González-Pastor S, López-González M, Simarro-Rueda E, Quintanilla-Mata ML, Matoses-Ruipérez ML, Ejarque-Vila L, Gall EC, Guirado L, Torra R, Ariceta G, Ars E (2021) Clinical and genetic characterization of a cohort of proteinuric patients with biallelic CUBN variants. Nephrol Dial Transplant. https://doi.org/10.1093/ndt/gfab285

    Article  Google Scholar 

  15. Yang J, Xu Y, Deng L, Zhou L, Qiu L, Zhang Y, Zhou J (2022) CUBN gene mutations may cause focal segmental glomerulosclerosis (FSGS) in children. BMC Nephrol 23:15. https://doi.org/10.1186/s12882-021-02654-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pediatric Nephrology, Marmara University School of Medicine, Fevzi Çakmak Mahallesi Muhsin Yazıcıoğlu Caddesi No: 10, Ust Kaynarca/Pendik, Istanbul, Turkey

    Neslihan Cicek, Harika Alpay, Sercin Guven, Özde Nisa Türkkan, Serim Pul, Ece Demirci, Nurdan Yıldız & Ibrahim Gokce

  2. Department of Medical Genetics, Marmara University School of Medicine, Fevzi Çakmak Mahallesi Muhsin Yazıcıoğlu Caddesi No: 10, Ust Kaynarca/Pendik, Istanbul, Turkey

    Ceren Alavanda & Pınar Ata

Authors
  1. Neslihan Cicek
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Harika Alpay
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sercin Guven
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ceren Alavanda
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Özde Nisa Türkkan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Serim Pul
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ece Demirci
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Nurdan Yıldız
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Pınar Ata
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ibrahim Gokce
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

N Çiçek and H Alpay participated in the study design. N Çiçek, N Yildiz and S Guven analyzed and interpreted the data. O Turkkan, S Pul, E Demirci collected the clinical and laboratory data. C Alavanda and P Ata analyzed and interpreted the genetic data. N Çiçek and H Alpay drafted the manuscript, and N Çiçek, I Gokce, N Yildiz and H Alpay reviewed the manuscript.

Each author contributed important intellectual content during manuscript drafting or revision and approved the final version.

Corresponding author

Correspondence to Neslihan Cicek.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Graphical Abstract (PPTX 45 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cicek, N., Alpay, H., Guven, S. et al. Clinical and genetic characterization of children with cubilin variants. Pediatr Nephrol 38, 1381–1385 (2023). https://doi.org/10.1007/s00467-022-05730-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-022-05730-y

Keywords

Search

Navigation