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Page 4 of 5 Gillion et al. Rare Dis Orphan Drugs J 2023;2:11 https://dx.doi.org/10.20517/rdodj.2022.23

Figure 2. Cubilin protein structure. Cubilin (CUB) is a 460 kDa glycoprotein without transmembrane domain. It acts as a receptor for
intrinsic factor-vitamin B12 complexes. There are 27 CUB domains. Intrinsic factor and vitamin B12 binding region is located in domains
5 to 8. The precise location of the binding sites for albumin remains unclear, but it is supposed to be located in the CUB domains near
the C-terminal area. IGS : Imerslund-Grasbëck syndrome; IF : intrinsic factor.

(EM) in three children with CUBN pathogenic variants. The authors suggested a role of podocyte
dysfunction together with a defect in the re-uptake of albumin in the proximal tubule of patients with
CUBN mutations. These data need to be confirmed. Indeed, these structural changes in podocytes were
absent in two children on EM . These authors showed that CUBN variants induce changes in the
[17]
scaffolding capabilities of cubilin protein in vitro. These changes reduce the interactions between CUB and
AMN, leading to an aberrant localization of AMN in the cytoplasm of proximal tubular cells instead of the
cell membrane. This may interrupt the receptor-mediated endocytosis that re-uptakes filtered albumin.

In conclusion, in the absence of functional cubilin in proximal tubular cells, albumin reabsorption is
incomplete and this leads to mild albuminuria. This mechanism acts downstream of the glomerular barrier
and does not affect the intraglomerular pressure and is thus not expected to damage podocytes. This
explains why anti-proteinuric agents such as ACE inhibitors do not succeed in lowering this particular
proteinuria. Detection of CUBN pathogenic variants is crucial in clinical nephrology because it prevents
unnecessary kidney biopsies but also the use of RAS blockers and their potential side effects such as
symptomatic hypotension or rarely angioneurotic edema. The benign course of this disease needs to be
confirmed by a longer follow-up.

DECLARATIONS
Authors’ contributions
Contributed to the concept, design, draft, and revision of this manuscript: Gillion V, Dahan K, Godefroid N

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Conflicts of interest
All authors declared that there are no conflicts of interest.

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