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

analysis, kidney ultrasound, and sometimes kidney biopsy. Proteinuria may be glomerular (mainly
albuminuria with or without microscopic hematuria), tubular (low molecular weight proteins such as α1-
microglobulin, retinol-binding protein, or β2-microglobulin), or both. Regardless of the cause of
proteinuria, blockers of the renin-angiotensin (RAS) system, such as angiotensin receptor blockers or
angiotensin-converting enzyme (ACE) inhibitors, are usually prescribed to decrease proteinuria and
therefore slow down kidney damage. Indeed, proteinuria is a well-established risk factor for progressive
kidney disease . Increased glomerular capillary pressure may induce excessive filtration of plasma proteins
[1,2]
and podocyte dysfunction. The increased reabsorption of plasma proteins by proximal tubular cells may be
toxic and lead to their apoptosis and to interstitial fibrosis . This paradigm recently changed with the
[1,3]
discovery of pathogenic variants in the cubilin (CUBN) gene that may cause nondetrimental proteinuria.
[4]
We report the case of 2 siblings with such variants and discuss their clinical management.

CLINICAL CASE
An 8-year-old girl of Turkish origin with no relevant medical history presented to the Pediatric Nephrology
clinic for nocturnal enuresis. An initial check-up revealed isolated mild proteinuria (protein/creatinine ratio
1.2 g/g) made up of albuminuria. The estimated glomerular filtration rate (eGFR) was normal as was the
ultrasound of the kidneys. A kidney biopsy was performed but only contained a single glomerulus with a
normal aspect by light microscopy. Immunofluorescence microscopy was negative. Enalapril was started at
2.5 mg/day. She remained on this medication for 15 years and proteinuria remained stable at 0.7 g/g to 1.2
g/g despite an increase in enalapril dosage up to 15 mg/day. Enalapril was poorly tolerated, with frequent
episodes of orthostatic hypotension. eGFR remained completely normal.

Her younger brother was also diagnosed with moderate isolated proteinuria (0.9 g/g) during a check-up for
hyperactive bladder. His kidney biopsy showed eight normal glomeruli by light microscopy.
Immunofluorescence microscopy was negative. Enalapril was started and proteinuria remained stable at
0.6-0.9 g/g during 8 years with preserved eGFR. Both parents have normal urinalysis without proteinuria.
The first genetic testing was performed in 2018 in both siblings with a panel including 20 genes related to
proteinuria. Results were not contributive as a single variant of unknown origin (VUS) of the ACTN4 gene
was found in the sister but not in her brother. Updated genetic testing performed in 2022 (NGS panel
[5]
enriched in 40genes important for proteinuric renal diseases) revealed in both siblings the presence of a
pathogenic nonsense variant (ACMG/AMP class 5) together with a potential splice disrupting variant
(ACMG/AMP class 3) in the CUBN (NM_001081.4):c.703 C > T (p.Arg235ter) and c.10363-3A > G (p.?).
Cubulin (CUBN) is dominated by 27 contiguous CUB domains, and variants occurring within the C-
terminal (after the CUB8 domain) are usually associated with isolated proteinuria. Here, p.R235* led to
truncation before CUB8, but none of the patients presented with low levels of vitamin B12 and
megaloblastic anemia Enalapril was therefore discontinued in both patients.

DISCUSSION
The proximal tubule reabsorbs large amounts of low-molecular-weight proteins but also albumin and
electrolytes from the glomerular filtrate. Megalin (LRP2), cubilin (CUBN), and amnionless protein (AMN)
are located in the apical part of proximal tubular cells and are responsible for receptor-mediated endocytosis
[3]
of proteins filtered through the glomerular barrier . Cubilin has been shown to have an essential role in
albumin reabsorption and is encoded by the CUBN gene [Figure 1] . Biallelic pathogenic variants in the
[6]
CUBN gene cause Imerslund-Gräsbeck syndrome (OMIM 261100), also called selective vitamin B12
[6]
(cobalamin) malabsorption with proteinuria . In this syndrome resulting in megaloblastic anemia
responsive to parenteral vitamin B12 therapy, half of the patients present with mild proteinuria and normal
eGFR. The mechanism of megaloblastic anemia is a defect in the receptor of the vitamin B12-intrinsic factor