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Link to original content: https://www.ncbi.nlm.nih.gov/omim/609342
Alternative titles; symbols
HGNC Approved Gene Symbol: CBLIF
SNOMEDCT: 234361004; ICD10CM: D51.0;
Cytogenetic location: 11q12.1 Genomic coordinates (GRCh38) : 11:59,829,273-59,845,499 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q12.1 | Intrinsic factor deficiency | 261000 | Autosomal recessive | 3 |
Hewitt et al. (1991) isolated a human gastric intrinsic factor cDNA clone using a rat cDNA clone as a probe. Comparison of the predicted amino acid sequences showed 80% identity between human and rat GIF.
By analysis of a panel of human/mouse somatic cell hybrids, Hewitt et al. (1991) mapped the GIF gene to human chromosome 11. Southern analysis of genomic DNA indicated the presence of a single human IF gene.
By fluorescence in situ hybridization and mouse/hamster somatic cell hybrid analysis, Fernandes et al. (1998) mapped the Gif gene to mouse chromosome 19. The high degree of homology of synteny between human 11q13 and mouse chromosome 19 suggests that the human GIF gene is located at 11q13.
Crystal Structure
Andersen et al. (2010) presented the crystal structure of the complex between GIF-cobalamin and the cubilin (CUBN; 602997)-GIF-cubilin-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 cubilin molecule by binding the 2 GIF domains in a calcium-dependent manner. This dual-point model provides a probable explanation of how cubilin indirectly induces ligand-receptor coupling. Finally, the comparison of calcium-binding CUB domains and the low-density lipoprotein receptor (LDLR; 606945)-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.
Gordon et al. (2004) sequenced all the exons of the GIF gene in 5 patients with intrinsic factor deficiency (IFD; 261000) and in the parents of 4 of the patients. A single-nucleotide substitution at position 2 of codon 5 (68A-G) in 1 or both copies of the GIF gene was identified in all of the subjects, with additional changes observed in 2 patients. When COS-7 cells were transfected with plasmids containing either the normal or the mutant cDNA, the secreted GIF proteins had a similar rate of secretion and sensitivity to pepsin degradation. Three subjects were homozygous for the missense mutation, changing codon 5 from CAG (glutamine) to CGG (arginine) (Q5R; 609342.0001). Three subjects were homozygous for the mutation and 2 subjects were heterozygous, 1 of whom was apparently a compound heterozygote at positions 1 and 2 of the fifth codon. The other patient heterozygous for position 2 had 1 heterozygous unaffected parent. Most parents were heterozygous for this base exchange, confirming the pattern of autosomal recessive inheritance for congenital IF deficiency. cDNA encoding GIF was mutated at basepair g.68A-G. The apparent size, secretion rate, and sensitivity to pepsin hydrolysis of the expressed IF were similar to native intrinsic factor. The allelic frequency of 68A-G was 0.067 and 0.038 in 2 control populations from Germany and Spain, respectively. Gordon et al. (2004) concluded that the Q5R variant was not the cause of the phenotype but was associated with congenital IF deficiency in such a way as to serve as a marker for inheritance of this disorder.
In an 11-year-old girl with severe anemia and cobalamin (Cbl) deficiency, Yassin et al. (2004) identified a 4-base deletion in the coding region of the GIF gene (609342.0002). The bone marrow showed frank megaloblastic morphology, and the Schilling test indicated a failure to absorb Cbl that was corrected by coadministration of intrinsic factor. Pentagastrin administration induced acid secretion, but the gastric juice lacked intrinsic factor as determined by Cbl binding and other tests.
In 7 families previously diagnosed with Imerslund-Grasbeck syndrome (261100) due to inconclusive results on radiocobalamin absorption tests, but who were negative for mutations in the cubilin (CUBN; 602997) or the AMN (605799) gene, Tanner et al. (2005) identified homozygosity for 6 different mutations in the GIF gene (609342.0002-609342.0007). Tanner et al. (2005) proposed that rather than radiocobalamin absorption tests, mutation analysis of the CUBN, AMN, and GIF genes may be the diagnostic method of choice for cobalamin absorption disorders.
Gordon et al. (2004) studied 5 patients with congenital intrinsic factor deficiency (IFD; 261000) and in all found the identical variant, 68A-G, in codon 5 of the GIF gene, changing the mature protein from glutamine to arginine at residue 5. Three subjects were homozygous for this base exchange and 2 were heterozygous. Since the apparent size, secretion rate, and sensitivity to pepsin hydrolysis of the intrinsic factor produced by mutation of the GIF gene and transfection into COS-7 cells were similar to native GIF, Gordon et al. (2004) concluded that the sequence aberration was not the cause of the phenotype but could serve as a marker for inheritance of the disorder. In 2 control populations, German and Spanish, the frequency of the change from A to G at nucleotide 68 was 0.067 and 0.038, respectively.
Tanner et al. (2005) analyzed exon 1 of the GIF gene in a set of 176 unrelated controls and found 140 homozygotes for the 68A allele, 6 homozygotes for the 68G allele, and 30 heterozygotes, resulting in an observed allele frequency of 0.119 for the 68G allele. They suggested that homozygosity for the 68G polymorphism has no clinical significance in IFD.
In an 11-year-old girl with severe anemia and cobalamin deficiency (IFD; 261000), Yassin et al. (2004) identified a 4-bp deletion (c183_186delGAAT) spanning positions 104 to 107 in exon 2 of the GIF gene as the basis of inherited intrinsic factor deficiency.
In an affected member of an African (Guinea-Bissau) family with hereditary intrinsic factor deficiency, Tanner et al. (2005) identified homozygosity for the 183delGAAT mutation, resulting in a frameshift at codon 61 predicted to lead to loss of function. The parents were heterozygous for the mutation.
In 2 affected members of a French family with hereditary intrinsic factor deficiency (IFD; 261000), Tanner et al. (2005) identified homozygosity for a G-to-A transition at +1 in the donor splice site of intron 1 of the GIF gene, predicted to lead to a loss of function. The parents were heterozygous for the mutation.
In 7 affected members of 2 Kuwaiti families with hereditary intrinsic factor deficiency (IFD; 261000), Tanner et al. (2005) identified homozygosity for a G-A transition at -1 in the acceptor splice site of intron 1 of the GIF gene that destroyed the consensus sequence and was predicted to lead to loss of function. The parents were heterozygous for the mutation.
In 4 affected members of a Turkish family with hereditary intrinsic factor deficiency (IFD; 261000), Tanner et al. (2005) identified homozygosity for a 137C-T transition in exon 2 of the GIF gene, replacing the conserved serine residue 46 with a leucine (S46L). The parents were heterozygous for the mutation.
In an affected member of a Turkish family with hereditary intrinsic factor deficiency (IFD; 261000), Tanner et al. (2005) identified homozygosity for a 1-bp deletion (161delA) in exon 2 of the GIF gene, resulting in a frameshift at codon 54 predicted to lead to loss of function. The parents were heterozygous for the mutation.
In an affected member of a Turkish family with hereditary intrinsic factor deficiency (IFD; 261000), Tanner et al. (2005) identified homozygosity for a 1-bp insertion (1175insT) in exon 8 of the GIF gene, resulting in a frameshift at codon 393 predicted to lead to loss of function. The parents were heterozygous for the mutation.
Andersen, C. B. F., Madsen, M., Storm, T., Moestrup, S. K., Andersen, G. R. Structural basis for receptor recognition of vitamin-B12-intrinsic factor complexes. Nature 464: 445-448, 2010. [PubMed: 20237569] [Full Text: https://doi.org/10.1038/nature08874]
Fernandes, M., Poirier, C., Lespinasse, F., Carle, G. F. The mouse homologs of human GIF, DDB1, and CFL1 genes are located on chromosome 19. Mammalian Genome 9: 339-342, 1998. [PubMed: 9530637] [Full Text: https://doi.org/10.1007/s003359900763]
Gordon, M. M., Brada, N., Remacha, A., Badell, I., del Rio, E., Baiget, M., Santer, R., Quadros, E. V., Rothenberg, S. P., Alpers, D. H. A genetic polymorphism in the coding region of the gastric intrinsic factor gene (GIF) is associated with congenital intrinsic factor deficiency. Hum. Mutat. 23: 85-91, 2004. [PubMed: 14695536] [Full Text: https://doi.org/10.1002/humu.10297]
Hewitt, J. E., Gordon, M. M., Taggart, R. T., Mohandas, T. K., Alpers, D. H. Human gastric intrinsic factor: characterization of cDNA and genomic clones and localization to human chromosome 11. Genomics 10: 432-440, 1991. [PubMed: 2071148] [Full Text: https://doi.org/10.1016/0888-7543(91)90329-d]
Tanner, S. M., Li, Z., Perko, J. D., Oner, C., Cetin, M., Altay, C., Yurtsever, Z., David, K. L., Vaivre, L., Ismail, E. A., Granbeck, R., de la Chapelle, A. Hereditary juvenile cobalamin deficiency caused by mutations in the intrinsic factor gene. Proc. Nat. Acad. Sci. 102: 4130-4133, 2005. [PubMed: 15738392] [Full Text: https://doi.org/10.1073/pnas.0500517102]
Yassin, F., Rothenberg, S. P., Rao, S., Gordon, M. M., Alpers, D. H., Quadros, E. V. Identification of a 4-base deletion in the gene in inherited intrinsic factor deficiency. Blood 103: 1515-1517, 2004. [PubMed: 14576042] [Full Text: https://doi.org/10.1182/blood-2003-07-2239]