A number sign (#) is used with this entry because of evidence that chronic benign proteinuria (PROCHOB) is caused by homozygous or compound heterozygous mutation in the CUBN gene (602997) on chromosome 10p13.

Biallelic mutation in the CUBN gene can also cause Imerslund-Grasbeck syndrome-1 (IGS1; 261100), which shows overlapping features.

Chronic benign proteinuria (PROCHOB) is an autosomal recessive condition characterized by onset of isolated proteinuria in the first decade of life. The proteinuria is nonprogressive; affected individuals do not develop renal disease or impaired kidney function, and they do not have additional associated abnormalities, such as hypertension. The correct diagnosis is important to avoid inefficient or invasive intervention, such as medication or renal biopsy (summary by Bedin et al., 2020).

Bedin et al. (2020) identified 39 patients, mostly French, who presented with chronic isolated proteinuria with onset in the first decade. The patients were ascertained from 3 large cohorts of patients with suspected genetic renal disease or with chronic proteinuria. The average age at discovery of proteinuria was 10.9 years. Although not measured in all cases, the urinary proportion of albumin was higher than 50%, and urinary microglobulins, such as B2M (109700), were mostly low or absent. Renal biopsies, performed in 19 patients, showed minimal, nonspecific, or, most commonly, absence of any pathologic lesions. Several patients were treated with ACE inhibitors, with no protein-lowering effect. In all cases, renal function was normal at an average age of 17, and it was normal in the oldest patient at age 66. The affected individuals showed only a normal age-related decline in glomerular filtration rate (GFR), indicating that the PROCHOB condition is not progressive itself. None had signs of vitamin B12 deficiency, neurologic symptoms, or megaloblastic anemia. Bedin et al. (2020) concluded that PROCHOB is a benign condition.

The transmission pattern of PROCHOB in the families reported by Bedin et al. (2020) was consistent with autosomal recessive inheritance.

In 39 patients with PROCHOB, Bedin et al. (2020) identified over 30 novel variants in the CUBN gene (see, e.g., 602997.0007-602997.0010). The variants, which were found by next-generation sequencing and confirmed by Sanger sequencing, segregated with the phenotype in families from which parental DNA was available. All variants were either absent from or had low frequencies (less than 0.1%) in public reference databases, such as gnomAD, and in an in-house genome database. Almost all variants affected residues or led to premature termination of the protein after the CUB8 domain (residues 1487-3618), which is in contrast to mutations associated with IGS1 that tend to occur before the CUB8 domain (residues 66-1390). These C-terminal mutations associated with PROCHOB affected residues after the vitamin B12-binding domain, leaving that function intact. Two patients carried CUBN variants (T55M and W1158X) that occurred earlier in the protein, but they were in trans with variants affecting residues after the CUB8 domain. The findings indicated a specific association between isolated benign proteinuria and C-terminal CUBN variants. Functional studies of the variants and studies of patient cells were not performed, but structural modeling predicted that the mutations would have different detrimental effects on cubilin function, including abnormal folding or structure of the protein, instability, or interference with ligand binding. The authors also presented some evidence that C-terminal variants in the CUBN gene may also be associated with albuminuria and slightly increased GFR in the general population.

By whole-exome sequencing (WES) in 2 brothers of Senegalese ancestry (CIC02583 and CIC02585) with proteinuria, Mejecase et al. (2019) identified compound heterozygosity for a nonsense (R2636X) and a missense (C3448W) mutation in the CUBN gene. Both brothers as well as their older brother exhibited features of retinitis pigmentosa (RP93; 619845); all 3 were compound heterozygous for mutations in the CC2D2A gene (612013.0010-612013.0011). The proband, who also had achromatopsia (ACHM2; 216900), was homozygous for a frameshift mutation in the CNGA3 gene (600053.0011) as well. The respective variants segregated fully with disease in the family, and the authors noted that their case report illustrated the power of WES to elucidate complex phenotypes segregating within a family.