Alternative titles; symbols
HGNC Approved Gene Symbol: CUBN
SNOMEDCT: 234363001; ICD10CM: D51.1;
Cytogenetic location: 10p13 Genomic coordinates (GRCh38): 10:16,823,966-17,129,811 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10p13 | [Proteinuria, chronic benign] | 618884 | Autosomal recessive | 3 |
| Imerslund-Grasbeck syndrome 1 | 261100 | Autosomal recessive | 3 |
Cubilin is the intestinal receptor for the endocytosis of intrinsic factor (IF; 609342)-vitamin B12 and a receptor in epithelial apoA-I/HDL (see 107680) metabolism (summary by Kozyraki et al., 1998).
By surface plasmon resonance analysis of ligand-affinity-purified human cubilin, Kozyraki et al. (1998) demonstrated a high affinity calcium- and cobalamin (vitamin B12)-dependent binding of gastric intrinsic factor (IF)-cobalamin. Complete cDNA cloning of the human receptor showed a 3,598-amino acid peripheral membrane protein with 69% identity to rat cubilin. Amino-terminal sequencing of the receptor indicated that the cDNA sequence encodes a precursor protein undergoing proteolytic processing due to cleavage at a recognition site (arg-7/glu-8/lys-9/arg-10) for the trans-Golgi proteinase furin (136950).
Using fluorescence in situ hybridization, radiation hybrid mapping, and screening of YAC clones, Kozyraki et al. (1998) mapped the human cubilin gene between markers D10S1661 and WI-5445 on the short arm of chromosome 10. This was within the 6-cM region harboring the gene responsible for megaloblastic anemia-1 (MGA1; 261100). All of this was considered circumstantial evidence that an impaired synthesis, processing, or ligand binding of cubilin is the molecular basis of Imerslund-Grasbeck disease (MGA1).
Studies in rodents showed that uptake of cobalamin in complex with IF is facilitated by an intestinal 460-kD protein (Birn et al., 1997; Seetharam et al., 1997), designated cubilin (Moestrup et al., 1998). Cubilin is suggested to traffic by means of megalin (LRP2; 600073), a 600-kD endocytic receptor expressed in the same tissues and mediating uptake of a number of ligands, including transcobalamin-cobalamin complexes. Like megalin, cubilin has a significantly higher expression in the renal proximal tubules compared with the intestine, and, because IF is only present in minute amounts in nongastrointestinal tissues, cubilin might also have multiligand properties. Cubilin binds receptor-associated protein (RAP; 104225), a 40-kD endoplasmic reticulum protein also binding with high affinity to the multiligand giant receptors (e.g., megalin) belonging to the low density lipoprotein receptor (LDLR; 606945) protein family. RAP may function as a chaperone during folding of the receptors. Moestrup et al. (1998) determined the primary structure of rat cubilin and showed that almost the entire sequence is accounted for by a cluster of 8 epidermal growth factor (EGF) repeats, followed by a large cluster of 27 CUB domains which led to the designation of the receptor. (The name CUB, introduced by Bork and Beckmann (1993), is an abbreviation for complement subcomponents C1r/C1s (613785; 120580), Uegf, and bone morphogenetic protein-1 (BMP1; 112264).)
Although cubilin is the intestinal receptor for the endocytosis of intrinsic factor-vitamin B12, several lines of evidence, including a high expression in kidney and yolk sac, indicated that it may have additional functions. Using cubilin affinity chromatography, Kozyraki et al. (1999) isolated apolipoprotein A-I (APOA1; 107680), the main protein of high density lipoprotein (HDL). They demonstrated a high-affinity binding of APOA1 and HDL to cubilin, and cubilin-expressing yolk sac cells showed efficient endocytosis of iodine-labeled HDL that could be inhibited by IgG antibodies against APOA1 and cubilin. The physiologic relevance of the cubilin-APOA1 interaction was further emphasized by urinary APOA1 loss in some known cases of functional cubilin deficiency (Imerslund-Grasbeck syndrome). Therefore, cubilin is a receptor in epithelial APOA1/HDL metabolism.
Megalin binds a large number of structurally unrelated ligands, and coreceptors may confer ligand specificity by sequestering and presenting their cargo to megalin. For example, IF-B12 complex is taken up in the intestine by a tandem receptor-mediated mechanism; the complex is first bound to a receptor, cubilin, anchored to the outer leaflet of the plasma membrane possibly by an amphipathic helix, followed by endocytosis of cubilin and its cargo mediated by megalin. The pivotal role of intestinal cubilin is underscored by the vitamin B12 deficiency observed in patients with Imerslund-Grasbeck disease characterized by defective cubilin incapable of binding IF-B12. These patients have low molecular weight (LMW) proteinuria in addition to megaloblastic anemia, indicating dysfunction of cubilin coexpressed with megalin in kidney proximal tubules (summary by Nykjaer et al., 2001).
Nykjaer et al. (2001) identified cubilin as an important coreceptor in the endocytic pathway for retrieval of 25(OH)D3-DBP complexes by megalin-mediated endocytosis in the kidney. They showed that absence of cubilin or inhibition of its function markedly reduces cellular uptake of the steroid-carrier complex, and animals or patients lacking functional cubilin are characterized by abnormal vitamin D metabolism. They identified patients with mutations in an endocytic pathway that regulates steroid hormone metabolism.
Cubilin recognizes intrinsic factor (IF)-cobalamin and various other proteins to be endocytosed in the intestine and kidney, respectively. Fyfe et al. (2004) showed that cubilin and amnionless (AMN; 605799) colocalize in the endocytic apparatus of polarized epithelial cells and copurify as a tight complex during IF-cobalamin affinity and nondenaturing gel filtration chromatography. In transfected cells expressing either AMN or a truncated IF-cobalamin-binding cubilin construct, neither protein alone conferred ligand endocytosis. Other studies indicated that cubilin and AMN are subunits of a novel cubilin/AMN (cubam) complex, where AMN binds to the N-terminal third of cubilin and directs subcellular localization and endocytosis of cubilin with its ligand. Fyfe et al. (2004) concluded that mutations affecting either of the 2 proteins may abrogate function of the cubam complex and cause Imerslund-Grasbeck syndrome.
Crystal Structure
Andersen et al. (2010) presented the crystal structure of the complex between gastric intrinsic factor (IF; 609342)-cobalamin and the CUBN-IF-cobalamin-binding region determined at 3.3-angstrom resolution. The structure provided insight into how several CUB (complement C1r/C1s, Uegf, Bmp1) domains collectively function as modular ligand-binding regions, and how 2 distant CUB domains embrace the cobalamin molecule by binding the 2 IF domains in a calcium-dependent manner. This dual-point model provided a probable explanation of how cobalamin indirectly induces ligand-receptor coupling. Finally, the comparison of calcium-binding CUB domains and the LDLR-type A modules suggested that the electrostatic pairing of a basic ligand arginine/lysine residue with calcium-coordinating acidic aspartates/glutamates is a common theme of calcium-dependent ligand-receptor interactions.
Imerslund-Grasbeck Syndrome 1
In affected members of 15 of 17 Finnish families with Imerslund-Grasbeck syndrome-1 (IGS1; 261100), Aminoff et al. (1999) identified a homozygous missense mutation in the CUBN gene (P1297L; 602997.0001). The mutation, which was found by a combination of linkage analysis and candidate gene sequencing, segregated with the disorder in the families. It was present in 1 of 316 Finnish controls, yielding a carrier rate of 0.3% in that population. Western blot analysis of patient urine samples showed normal expression of the mutant protein; additional functional studies were not performed. The findings were consistent with a founder effect. Affected members of another Finnish family with the disorder were homozygous for a splice site mutation (602997.0002); Western blot analysis of patient urine samples did not detect any CUBN protein, consistent with a loss of function.
Nykjaer et al. (2001) found that a patient with IGS1 who was homozygous for a splice site mutation in the CUBN gene (602997.0002) showed urinary loss of vitamin D-binding protein (VDBP; 139200) and 25(OH)D3. On the other hand, patients with the missense mutation P1297L (602997.0001) reabsorbed VDBP normally, suggesting that the binding site for 25(OH)D3-DBP is distinct from the binding site for IF-B12.
In a patient with IGS1, Storm et al. (2011) identified homozygosity for a splice site mutation in the CUBN gene (602997.0003). This patient showed no immunogenic reaction to cubilin and was found to have an abnormal cytoplasmic, vesicular distribution of AMN, its receptor partner, in renal biopsy specimen, indicating that AMN depends on cubilin for correct localization in the human proximal tubule.
Chronic Benign Proteinuria
In 39 patients with chronic benign proteinuria (PROCHOB; 618884), 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 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, which occur before the CUB8 domain (residues 66-1390). The only 2 CUBN variants before CUB8 found in patients with PROCHOB (T55M and W1158X) 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 glomerular filtration rate (GFR) in the general population.
Storm et al. (2013) reported 3 patients from 2 unrelated families with IGS1. Family 5 was a consanguineous Tunisian family with a homozygous G1112E mutation in the CUBN gene (602997.0005), and family 6 was a nonconsanguineous Finnish family with the homozygous founder Finnish mutation (P1297L; 602997.0001). Clinical details were limited, but all patients had megaloblastic anemia unrelated to intrinsic factor. However, only the Tunisian patients had LMW proteinuria with significantly increased excretion of cubulin ligands, including transferrin (TF; 190000), apo A-I (APOA1; 107680), albumin (ALB; 103600), VDBP (139200), and A1M (176870). In vitro functional expression studies in transfected CHO cells showed that the G1112E mutation, in the CUB6 domain, resulted in the absence of CUBN expression at the cell surface. In contrast, the P1297L mutation in the CUB8 domain was predicted not to affect CUBN cell surface expression (Kristiansen et al., 2000). Storm et al. (2013) concluded that different mutations may have different functional effects on CUBN receptor function, resulting in phenotypic differences.
Ciancio et al. (2019) reported 4 sibs, born of unrelated parents of Ashkenazi Jewish descent, with IGS1 caused by a homozygous frameshift mutation in the CUBN gene (c.2614delGA; 602997.0006). In addition, all patients had profound vitamin D deficiency requiring supplementation. Ciancio et al. (2019) concluded that null CUBN mutations may affect absorption of the VDBP protein, resulting in vitamin D deficiency; this suggested a possible genotype/phenotype correlation. Functional studies of the variant and studies of patient cells were not performed.
Bedin et al. (2020) found that C-terminal mutations in the CUBN gene that occurred after the CUB8 domain were associated with isolated chronic benign proteinuria (PROCHOB; 618884) without megaloblastic anemia or B12 deficiency. The identified mutations affected residues in the CUBN protein after the vitamin B12-binding domain, thus leaving that function intact.
Mixed breed dogs exhibiting autosomal recessive inheritance of cubilin malexpression have been reported (Fyfe et al., 1991; Xu et al., 1999). In these dogs, Nykjaer et al. (2001) showed that there is a disturbance of vitamin D metabolism as well as severe vitamin B12 deficiency similar to that of patients with Imerslund-Grasbeck disease.
Megaloblastic anemia and neurologic disturbances are common symptoms of deficiency of the coenzyme vitamin B12 (cyanocobalamin). The cellular uptake of the vitamin and its modified forms depends on the binding to the carrier proteins, intrinsic factor (IF; 609342) produced in the stomach, and transcobalamin, present in the circulation and various tissue fluids. Hereditary forms of cobalamin deficiency are known to relate to qualitatively abnormal IF (see 261000), to decreased synthesis of transcobalamin (275350), and to a defect of the intestinal epithelium leading to decreased uptake of IF-cobalamin and failure to absorb cobalamin (Imerslund-Grasbeck disease). Imerslund-Grasbeck disease-1 has been shown by linkage studies to be caused by mutation in a region designated MGA1 (megaloblastic anemia-1), located on 10p between markers D10S548 and D10S466. The defect has been thought to be related to abnormal epithelial translocation of cobalamin, perhaps due to decreased receptor function/expression.
In affected members of 15 of 17 Finnish families with Imerslund-Grasbeck syndrome-1 (IGS1; 261100), Aminoff et al. (1999) identified a homozygous c.3916C-T transition in the CUBN gene, resulting in a pro1297-to-leu (P1297L) substitution. The mutation, which was found by a combination of linkage analysis and candidate gene sequencing, segregated with the disorder in the families. It was present in 1 of 316 Finnish controls, yielding a carrier rate of 0.3% in that population. Western blot analysis of patient urine samples showed normal expression of the mutant protein; additional functional studies were not performed. The findings were consistent with a founder effect.
By site-directed mutagenesis, mammalian expression, and functional comparison of the purified wildtype and Finnish mutant forms of the IF-cobalamin-binding region of cubilin (amino acids 928-1386), Kristiansen et al. (2000) investigated the functional implications of the P1297L mutation. They found that the mutation impairs recognition of intrinsic factor-vitamin B12 complex by cubilin.
In a Finnish patient (family 6) with IGS1 but only trace proteinuria, Storm et al. (2013) identified a homozygous c.3890C-T transition in exon 27 of the CUBN gene, resulting in the P1297L substitution in the CUB8 domain. In contrast, the P1297L mutation in domain CUB8 was predicted not to affect CUBN cell surface expression (Kristiansen et al., 2000).
In affected members of a Finnish family with Imerslund-Grasbeck syndrome-1 (IGS1; 261100), Aminoff et al. (1999) identified an intronic C-to-G transversion in the CUBN gene. The mutation interrupted CUB domain 6 and was predicted to result in splice site alterations and the production of abnormally truncated proteins. The variant was not found in 302 control Finnish chromosomes. Western blot analysis of patient urine samples did not detect any CUBN protein, consistent with a loss of function. Tanner et al. (2004) clarified this mutation, which is a c.3300-439C-G transversion in intron 23 of the CUBN gene, resulting in complex abnormal splicing and a frameshift.
In a patient with Imerslund-Grasbeck syndrome-1 (IGS1; 261100), Storm et al. (2011) identified a homozygous G-to-T transversion at the conserved donor splice site of exon 23 of the CUBN gene. A renal biopsy specimen from the patient showed no immunologic reaction for cubilin, consistent with a loss-of-function effect. There was also abnormal cytoplasmic vesicular distribution of amnionless (AMN; 605799), indicating that amnionless depends on cubilin for correct localization in the human proximal tubule.
In a 15-year-old German girl, born of unrelated parents, with Imerslund-Grasbeck syndrome-1 (IGS1; 261100), Hauck et al. (2008) identified a heterozygous c.1010C-T transition in the CUBN gene, resulting in a pro337-to-leu (P337L) substitution inherited from her unaffected father. The other allele carried a heterozygous large deletion encompassing the entire CUBN gene as well as about 150-kb up- and downstream from the gene boundaries. The deletion was presumably inherited from the mother, although DNA from the mother was not available. Functional studies of the variant and studies of the variant in patient cells were not performed.
In 2 Tunisian patients, born of consanguineous parents, with Imerslund-Grasbeck syndrome-1 (IGS1; 261100), Storm et al. (2013) identified a homozygous c.3335G-A transition (c.3335G-A, NM_001082.3) in exon 24 of the CUBN gene, resulting in a gly1112-to-glu (G1112E) substitution in the CUB6 domain. In vitro functional expression studies in transfected CHO cells showed that the G1112E mutation resulted in the absence of CUBN expression at the cell surface. The patients had significant proteinuria in addition to megaloblastic anemia.
In 4 sibs, born of unrelated parents of Ashkenazi Jewish background, with Imerslund-Grasbeck syndrome-1 (IGS1; 261100), Ciancio et al. (2019) identified a homozygous 2-bp deletion (c.2614_2615delGA, NM_001081.3) in the CUBN gene, resulting in a frameshift and premature termination (Asp872LeufsTer3). The mutation was predicted to result in nonsense-mediated mRNA decay and complete loss of the CUBN protein. In addition, all patients had profound vitamin D deficiency requiring supplementation. Ciancio et al. (2019) concluded that null CUBN mutations may affect absorption of the VDBP protein, resulting in vitamin D deficiency; this suggested a possible genotype/phenotype correlation. Functional studies of the variant and studies of patient cells were not performed. The authors stated that this mutation is a founder mutation in the Ashkenazi Jewish population.
In 5 French patients, including 3 sibs (family 7), with chronic benign proteinuria (PROCHOB; 618884), Bedin et al. (2020) identified a homozygous c.9053A-C transversion in exon 57 of the CUBN gene, resulting in a tyr3018-to-ser (Y3018S) substitution. The families were identified as families 7, 8, and 26. Three additional patients (families 19, 20, and 32) were compound heterozygous for Y3018S and a splice site (c.5549-2A-C in family 19) or nonsense mutation. Patient 20 had a c.3473G-A transition in exon 24, resulting in a trp1158-to-ter (W1158X; 602997.0008) substitution on the other allele, and patient 32 had a c.10852C-T transition in exon 67, resulting in an arg3618-to-ter (R3618X; 602997.0009) substitution on the other allele. The mutations, which were found by next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families from which parental DNA was available. The variants were either absent from databases such as gnomAD or present at very low frequencies in heterozygous state only. Functional studies of the variants and studies of patient cells were not performed.
For discussion of the c.3473G-A transition in exon 24 of the CUBN gene, resulting in a trp1158-to-ter (W1158X) substitution, that was found in compound heterozygous state in a patient with chronic benign proteinuria (PROCHOB; 618884) by Bedin et al. (2020), see 602997.0007.
For discussion of the c.10852C-T transition in exon 67 of the CUBN gene, resulting in an arg3618-to-ter (R3618X) substitution, that was found in compound heterozygous state in a patient with chronic benign proteinuria (PROCHOB; 618884) by Bedin et al. (2020), see 602997.0007.
In a patient (family 11) with chronic benign proteinuria (PROCHOB; 618884) Bedin et al. (2020) identified a homozygous c.8465C-T transition in exon 54 of the CUBN gene, resulting in a pro2822-to-leu (P2822L) substitution. The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing, was filtered against public databases. Parental DNA was not available for segregation studies. Functional studies of the variant and studies of patient cells were not performed.
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