CUBN gene mutations may cause focal segmental glomerulosclerosis (FSGS) in children

Abstract

Background: Imerslund-Gräsbeck Syndrome (IGS) is mainly caused by CUBN gene biallelic mutations. Proteinuria accompanies IGS specific symptoms in about half of the patients, isolated proteinuria is rarely reported. Here we present 3 patients with isolated proteinuria and focal segmental glomerulosclerosis (FSGS) caused by CUBN gene biallelic pathogenic variants.

Method: Whole exome sequencing was performed on three children with isolated proteinuria. CUBN gene biallelic pathogenic variants were found and then verified by sanger sequencing. Their clinical, pathological and molecular genetic characteristics were analyzed and correlated accordingly.

Results: All three children presented with isolated proteinuria, no megaloblastic anemia. Their urine levels of β2 microglobulin were normal or slightly higher. Renal biopsies showed focal segmental glomerulosclerosis with mild glomerular mesangial hypercellularity, partial effacement of foot processes and podocyte microvillation. Two of them were found to carry compound heterozygous mutations and one homozygous mutation of CUBN gene. Totally four CUBN gene biallelic pathogenic variants were identified, including c.9287 T > C (p.L3096P), c.122 + 1G > A, c.7906C > T (p.R2636*), c.10233G > A (p.W3411*). Except for intron splice-site mutation, all other variants are located in highly conserved sites of CUB domain for binding to albumin.

Conclusion: The results demonstrate that CUBN gene mutations may cause isolated proteinuria pathologically presented as FSGS. Our cases extend the spectrum of renal manifestation and genotype of CUBN gene mutations.

Keywords: CUBN gene; Focal segmental glomerulosclerosis; Gene mutation; Podocyte; Proteinuria.

Fig. 1

The renal pathologies of three patients. Kidney pathologies of three patients under light microscope are showing in Fig. 1 A-D. All of them have focal segmental glomerulosclerosis, mild mesangial cell proliferation, and interstitial fibrosis. (A) shows focal segmental glomerular sclerosis (pointed by red arrow) from patient 1. (B) and (C) show crescents in renal pathologies respectively from patient 1 and patient 2. (D) shows interstitial fibrosis (pointed by red arrow) from patient 1. podocyte pathologies of three patients under electron microscopy are showing in Fig. 1 E-F. All of them have effacement of foot processes and podocyte microvillation. (E) shows podocyte microvillation (pointed by red arrow) from patient 1. (F) shows effacement of foot processes (pointed by red arrow) from patient 2

Fig. 2

Family diagram of the three patients. A, B, C indicate patient 1, 2, 3 respectively

Fig. 3

sanger sequencing confirmation and conservation analysis of CUBN gene mutations in three families. (A) Compound heterozygous mutation of CUBN gene in patient 1, his patients carry heterozygous CUBN gene mutation of c.122 + 1G > A and c.9287 T > C, respectively. (B) Compound heterozygous mutation of CUBN gene in patient 2, his patients carry heterozygous CUBN gene mutation of c.7906C > T and c.9287 T > C, respectively. (C) homozygous mutation c.10233G > A of CUBN gene in patient 3 and his patients. (D) Position of the CUBN variants along the cubilin protein. (E) Conservation of L3096, R2636 and W3411 (blue rectangle showed) in CUBN gene among different species. Wt: wild type; hom: homozygous; het: heterozygous

Fig. 4

Protein modelling of CUBN variants. (A) CUBN are shown in ribbon format, colored green, pink, and purple, the purple indicates CUBN residue 3096. (B) The 3D-structure model and surface model between wild-type cubilin protein and variant cubilin protein