Alternative titles; symbols
HGNC Approved Gene Symbol: MIP
Cytogenetic location: 12q13.3 Genomic coordinates (GRCh38): 12:56,449,502-56,456,553 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q13.3 | Cataract 15, multiple types | 615274 | Autosomal dominant | 3 |
The major intrinsic protein of the ocular lens fiber membrane (MIP) is an abundant protein that appears during differentiation of the ocular lens and has a molecular mass of about 26 kD. The bovine MIP gene was isolated by Gorin et al. (1984). Pisano and Chepelinsky (1991) reported the entire nucleotide sequence of the MIP gene.
Pisano and Chepelinsky (1991) reported the genomic structure of the MIP gene. The gene spans 3.6 kb, contains 4 exons, and is present in single copy in the haploid human genome. Transcription is initiated from a single site 26 nucleotides downstream from the TATA box.
Wang et al. (1995) mapped 2 negative regulatory elements in the MIP 5-prime noncoding region and demonstrated that the promoter is active in lens cells but not in kidney epithelial cells or mouse fibroblasts.
Gonen et al. (2004) determined the structure of the aquaporin-0 membrane junction by electron crystallography. The junction is formed by 3 localized interactions between AQP0 molecules in adjoining membranes, mainly mediated by proline residues conserved in AQP0s from different species but not present in most other aquaporins. Whereas all previously determined aquaporin structures showed the pore in an open conformation, the water pore was closed in AQP0 junctions. The authors also observed an additional pore constriction in the water pathway in AQP0 not seen in other aquaporin structures that may be responsible for pore gating.
Gonen et al. (2005) described a 1.9-angstrom structure of junctional AQP0, determined by electron crystallography of double-layered 2-dimensional crystals. Comparison of junctional and nonjunctional AQP0 structures showed that junction formation depends on a conformational switch in an extracellular loop, which may result from cleavage of the cytoplasmic amino and carboxy termini. In the center of the water pathway, the closed pore in junctional AQP0 retains only 3 water molecules, which are too widely spaced to form hydrogen bonds with each other. Packing interactions between AQP0 tetramers in the crystalline array are mediated by lipid molecules, which assume preferred conformations. Gonen et al. (2005) were therefore able to build an atomic model for the lipid bilayer surrounding the AQP0 tetramers, and to describe lipid-protein interactions.
Sparkes et al. (1985) used a bovine MIP probe in Southern analysis of somatic cell hybrids to assign the human MIP gene to chromosome 12. Using hybrid cells with various deletions and rearrangements of human 12, they further assigned the gene to 12cen-q14. By in situ hybridization, Griffin and Shiels (1992) assigned the MIP gene to 12q14. This region of human chromosome 12 is one of conservation of synteny with mouse chromosome 10. The mouse locus, Mip, maps near the Cat locus at the distal end of mouse chromosome 10 (Peters, 1990; Griffin and Shiels, 1992).
Ma et al. (1997) referred to the MIP26 gene as AQP0 and demonstrated that, although it is located in 12q13, it is not in the same 200-kb YAC clone that contains AQP2, AQP5 (600442), and AQP6 (601383); the latter 3 genes span only approximately 27 kb.
Using 2-color fluorescence in situ hybridization on high-resolution R-banded chromosomes and human genomic DNA clones for aquaporin-2 (AQP2; 107777) and MIP as probes, Saito et al. (1995) found that both genes are located in close proximity in region 12q13. MIP appeared to be distal to AQP2.
Berry et al. (2000) identified mutations in the MIP gene in 2 families with autosomal dominant cataract (154050.0001-154050.0002). Affected members of one family had discrete, congenital, isolated, progressive, bilateral, punctate lens opacities limited to mid- and peripheral lamellae; some individuals had asymmetric anterior and posterior polar opacification, and one, predominantly cortical cataract, thus prompting Berry et al. (2000) to describe the cataract as polymorphic. Another family manifested isolated, fine, nonprogressive, congenital lamellar and sutural opacification.
Francis et al. (2000) used the Xenopus laevis oocyte expression system to demonstrate that MIP proteins with either the T138R (154050.0001) or E134G (154050.0002) mutation caused loss of membrane water channel activity due to impaired trafficking of the mutant protein to the oocyte plasma membrane. Although missense mutations in AQP1 (107776) and AQP2 proteins are known to result in recessive traits in vivo and in vitro, when E134G or T138R is coexpressed with wildtype AQP0 protein, the mutant protein exhibits dominant-negative behavior. The authors hypothesized that less severe defects in the AQP0 protein may contribute to lens opacity in patients with common, less fulminant forms of cataract.
In affected members of a family segregating autosomal dominant cataract, previously reported by Bateman et al. (1986) and mapped to chromosome 12q13 by Bateman et al. (2000), Geyer et al. (2006) identified a frameshift mutation in the MIP gene (3223delG; 154050.0003).
Shiels and Bassnett (1996) demonstrated that distinct mutations in the murine Mip gene underlie one form of autosomal dominant cataract in the mouse. The cataract Fraser mutation is a transposon-induced splicing error that substitutes a long terminal repeat sequence for the carboxy-terminus of MIP. The lens opacity mutation is an amino acid substitution that inhibits targeting of MIP to the cell membrane. The authors stated that these allelic cataract mutations provided the first direct evidence that MIP plays a crucial role in the development of a transparent eye lens. The cataract Fraser mutation, originally called 'Shrivelled' by Fraser and Schabtach (1962), maps near the distal end of mouse chromosome 10 where the MIP gene had been mapped by Griffin and Shiels (1992).
In a 4-generation pedigree segregating autosomal dominant cataract (CTRCT15; 615274), Berry et al. (2000) identified a C-to-G transversion, resulting in a threonine-to-arginine substitution at codon 138 (T138R) of the MIP gene. The mutation occurred in a highly conserved amino acid within transmembrane helix 4. All affected individuals had discrete, congenital, isolated, progressive, bilateral, punctate lens opacities limited to mid- and peripheral lamellae; some individuals had asymmetric anterior and posterior polar opacification, and one, predominantly cortical cataract, thus prompting Berry et al. (2000) to describe the cataract as polymorphic. The mutation was not found in 100 normal controls.
In a family with autosomal dominant congenital cataract in which all affected family members had isolated, fine, nonprogressive, congenital lamellar and sutural opacification (CTRCT15; 615274), Berry et al. (2000) identified an A-to-G transition in exon 2 of the MIP gene, resulting in a substitution of glycine for glutamic acid at codon 134 (E134G). The mutation occurred in a highly conserved amino acid located within transmembrane helix 4 and was predicted to affect the water channel or water transport through the channel. The mutation was not found in 100 normal controls.
In affected members of a family originally reported by Bateman et al. (1986) with autosomal dominant cataract (CTRCT15; 615274), Geyer et al. (2006) identified a 1-bp deletion (3223delG) within codon 235 in exon 4 of the MIP gene, causing a frameshift that alters 41 of 45 subsequent amino acids and creates a premature stop codon. Ten affected members exhibited variable expressivity of cataract with radiating, vacuolar, or dense opacities in the embryonal nucleus (Bateman et al., 1986; Bateman et al., 2000). Two additional members reported by Geyer et al. (2006) had milder and different cataracts with fine punctate cortical opacities. The mutation was not found in 11 unaffected family members tested.
Bateman, J. B., Johannes, M., Flodman, P., Geyer, D. D., Clancy, K. P., Heinzmann, C., Kojis, T., Berry, R., Sparkes, R. S., Spence, M. A. A new locus for autosomal dominant cataract on chromosome 12q13. Invest. Ophthal. Vis. Sci. 41: 2665-2670, 2000. [PubMed: 10937580]
Bateman, J. B., Spence, M. A., Marazita, M. L., Sparkes, R. S. Genetic linkage analysis of autosomal dominant congenital cataracts. Am. J. Ophthal. 101: 218-225, 1986. [PubMed: 3456204] [Full Text: https://doi.org/10.1016/0002-9394(86)90599-4]
Berry, V., Francis, P., Kaushal, S., Moore, A., Bhattacharya, S. Missense mutations in MIP underlie autosomal dominant 'polymorphic' and lamellar cataracts linked to 12q. Nature Genet. 25: 15-17, 2000. [PubMed: 10802646] [Full Text: https://doi.org/10.1038/75538]
Francis, P., Chung, J.-J., Yasui, M., Berry, V., Moore, A., Wyatt, M. K., Wistow, G., Bhattacharya, S. S., Agre, P. Functional impairment of lens aquaporin in two families with dominantly inherited cataracts. Hum. Molec. Genet. 9: 2329-2334, 2000. [PubMed: 11001937] [Full Text: https://doi.org/10.1093/oxfordjournals.hmg.a018925]
Fraser, F. C., Schabtach, G. 'Shrivelled': a hereditary degeneration of the lens in the house mouse. Genet. Res. 3: 383-387, 1962.
Geyer, D. D., Spence, M. A., Johannes, M., Flodman, P., Clancy, K. P., Berry, R., Sparkes, R. S., Jonsen, M. D., Isenberg, S. J., Bateman, J. B. Novel single-base deletional mutation in major intrinsic protein (MIP) in autosomal dominant cataract. Am. J. Ophthal. 141: 761-762, 2006. [PubMed: 16564824] [Full Text: https://doi.org/10.1016/j.ajo.2005.11.008]
Gonen, T., Cheng, Y., Sliz, P., Hiroaki, Y., Fujiyoshi, Y., Harrison, S. C., Walz, T. Lipid-protein interactions in double-layered two-dimensional AQP0 crystals. Nature 438: 633-638, 2005. Note: Erratum: Nature 441: 248 only, 2006. [PubMed: 16319884] [Full Text: https://doi.org/10.1038/nature04321]
Gonen, T., Sliz, P., Kistler, J., Cheng, Y., Walz, T. Aquaporin-0 membrane junctions reveal the structure of a closed water pore. Nature 429: 193-197, 2004. [PubMed: 15141214] [Full Text: https://doi.org/10.1038/nature02503]
Gorin, M. B., Yancey, S. B., Cline, J., Revel, J.-P., Horwitz, J. The major intrinsic protein (MIP) of the bovine lens fiber membrane: characterization and structure based on cDNA cloning. Cell 39: 49-59, 1984. [PubMed: 6207938] [Full Text: https://doi.org/10.1016/0092-8674(84)90190-9]
Griffin, C. S., Shiels, A. In situ hybridisation localises the gene for the major intrinsic protein of eye lens fibre cell membranes to human chromosome 12q14. Cytogenet. Cell Genet. 61: 8-9, 1992. [PubMed: 1505237] [Full Text: https://doi.org/10.1159/000133360]
Griffin, C. S., Shiels, A. Localisation of the gene for the major intrinsic protein of eye-lens-fibre cell membranes to mouse chromosome 10 by in situ hybridisation. Cytogenet. Cell Genet. 59: 300-302, 1992. [PubMed: 1544329] [Full Text: https://doi.org/10.1159/000133274]
Ma, T., Yang, B., Umenishi, F., Verkman, A. S. Closely spaced tandem arrangement of AQP2, AQP5, and AQP6 genes in a 27-kilobase segment at chromosome locus 12q13. Genomics 43: 387-389, 1997. [PubMed: 9268644] [Full Text: https://doi.org/10.1006/geno.1997.4836]
Peters, J. Mouse gene list. Mouse Genome 86: 24-80, 1990.
Pisano, M. M., Chepelinsky, A. B. Genomic cloning, complete nucleotide sequence, and structure of the human gene encoding the major intrinsic protein (MIP) of the lens. Genomics 11: 981-990, 1991. [PubMed: 1840563] [Full Text: https://doi.org/10.1016/0888-7543(91)90023-8]
Saito, F., Sasaki, S., Chepelinsky, A. B., Fushimi, K., Marumo, F., Ikeuchi, T. Human AQP2 and MIP genes, two members of the MIP family, map within chromosome band 12q13 on the basis of two-color FISH. Cytogenet. Cell Genet. 68: 45-48, 1995. [PubMed: 7525161] [Full Text: https://doi.org/10.1159/000133885]
Shiels, A., Bassnett, S. Mutations in the founder of the MIP gene family underlie cataract development in the mouse. Nature Genet. 12: 212-215, 1996. [PubMed: 8563764] [Full Text: https://doi.org/10.1038/ng0296-212]
Sparkes, R. S., Mohandas, T., Heinzmann, C., Gorin, M. B., Horwitz, J., Law, M. L., Jones, C., Bateman, J. B. The human gene for the major intrinsic protein (MIP) of the ocular lens fiber membrane is assigned to 12cen-q14. (Abstract) Cytogenet. Cell Genet. 40: 751, 1985.
Wang, X. Y., Ohtaka-Maruyama, C., Pisano, M. M., Jaworski, C. J., Chepelinsky, A. B. Isolation and characterization of the 5-prime-flanking sequence of the human ocular lens MIP gene. Gene 167: 321-325, 1995. [PubMed: 8566800] [Full Text: https://doi.org/10.1016/0378-1119(95)00637-0]