Alternative titles; symbols
HGNC Approved Gene Symbol: UTRN
Cytogenetic location: 6q24.2 Genomic coordinates (GRCh38) : 6:144,285,335-144,853,034 (from NCBI)
The UTRN gene encodes utrophin, a large skeletal muscle protein that shows similarities to dystrophin (DMD; 300377) (Burton et al., 1999)
Love et al. (1989) found that fragments from the C-terminal domain of DMD cDNA detected a closely related gene encoding a deduced 400-kD protein with 80% amino acid identity to that of dystrophin. The dystrophin-related sequence corresponded to a 13-kb mRNA transcript in human fetal muscle. The findings suggested that both dystrophin and the dystrophin-related protein are part of a family of functionally related large structural skeletal muscle proteins. Homologous genomic fragments were observed in chicken and horse DNA. Love et al. (1991) showed that the dystrophin-like (DMDL) gene was expressed in a wide range of human tissues. The transcript was particularly abundant in several fetal tissues including heart, placenta, and intestine.
Tinsley et al. (1992) cloned and sequenced the human DRP cDNA. The deduced 3,433-residue protein had a molecular mass of 395 kD. There was extensive homology between DRP and dystrophin.
Guo et al. (1996) cloned and sequenced a mouse utrophin cDNA and showed that it is homologous to the human utrophin gene, with 87% identity at the amino acid level.
Blake et al. (1995) identified a 5.5-kb UTRN mRNA tissue-specific transcript in adult mouse brain. This transcript, designated G-utrophin for ganglia, encoded a 113-kD protein that was the predominant utrophin transcript in the brain. During mouse embryogenesis, G-utrophin was seen in the developing sensory ganglia. Blake et al. (1995) noted that the DMD gene encodes several different transcripts, including Dp116, which is specific to peripheral nerve.
Using 5-prime RACE, Wilson et al. (1999) identified 2 novel transcripts of utrophin, Up71 and Up140, with unique first exons and promoters located in intron 62 and intron 44, respectively. The transcripts appeared to be structural homologs of the short dystrophin transcripts Dp140 and Dp71, thus further emphasizing the high degree of structural conservation between the utrophin and dystrophin genes. RT-PCR experiments demonstrated that Up71 and Up140 are widely expressed in both human and mouse tissues and, like Dp71, display tissue-specific differential splicing of exon 71. However, in contrast to Dp71, no evidence for alternative splicing of exon 78 was found for utrophin. The authors speculated that the latter observation may reflect a subtle functional difference in patterns of phosphorylation between the 2 proteins.
Burton et al. (1999) identified an alternative promoter lying within the large second intron of the UTRN gene, 50 kb 3-prime to exon 2. The promoter was highly regulated and appeared to drive transcription of a widely expressed unique first exon that splices into a common full-length mRNA at exon 3. The 2 utrophin promoters were independently regulated, and Burton et al. (1999) predicted that they respond to discrete sets of cellular signals.
Pearce et al. (1993) found that utrophin is encoded by multiple small exons spanning approximately 900 kb. In contrast to dystrophin, the utrophin gene has a long 5-prime untranslated region composed of 2 exons and a cluster of unmethylated, rare-cutting restriction enzyme sites at the 5-prime end.
Li et al. (2007) stated that the UTRN gene contains 74 exons.
Love et al. (1989) used human-rodent somatic cell hybridization to map the UTRN gene to chromosome 6q21-qter.
Buckle et al. (1990) localized the DMDL gene to human chromosome 6q24 by in situ hybridization using RFLP analysis in 2 mouse species. They localized the homologous Dmdl gene to mouse chromosome 10, proximal to the Myb oncogene.
Dystrophin is normally associated with a complex of muscle membrane (sarcolemmal) glycoproteins that provide a link to the extracellular matrix protein, laminin 2 (LAMA2; 156225). With the absence of dystrophin in Duchenne muscular dystrophy (DMD; 310200), there is a dramatic reduction of the dystrophin-associated glycoproteins; the same is true in 'mdx' mice, an animal model of Duchenne muscular dystrophy. In skeletal muscle biopsies from DMD patients and mdx mice, Matsumura et al. (1992) demonstrated that utrophin associated with an identical or antigenically similar complex of sarcolemmal proteins, and that utrophin and dystrophin-associated proteins colocalized to the neuromuscular junction. Both utrophin and the associated proteins were found throughout the sarcolemma in small-caliber skeletal muscles and cardiac muscle of adult mdx mice.
In mouse Sol8 muscle cells, Guo et al. (1996) found that expressed utrophin was targeted into agrin-induced acetylcholine receptor (AChR) clusters, while recombinant dystrophin was evenly distributed along cell membranes. The C-terminal region of utrophin was necessary for the association of utrophin with AChR clusters.
Prochniewicz et al. (2009) noted that utrophin and dystrophin bind actin with similar affinities, but the molecular contacts are different. Dystrophin utilizes 2 low-affinity actin-binding sites, whereas utrophin utilizes a continuous actin-binding domain. Using transient phosphorescence anisotropy, they showed that both proteins restricted the amplitude and increased the rate of actin bending and twisting. However, utrophin had a much greater effect than dystrophin in reducing actin torsional rigidity, particularly with high actin saturation. Utrophin, like dystrophin, had no effect on actin aggregation or bundling. Prochniewicz et al. (2009) hypothesized that, in addition to stabilizing actin filaments from depolymerization, dystrophin and utrophin provide greater resistance to actin filament breakage due to stretching or twisting.
Hilton-Jones and Squier (1993) stated that no clinical disorders relating to altered dystrophin-related protein had been identified.
Li et al. (2007) provided evidence that UTRN acts as a tumor suppressor gene. UTRN expression was downregulated in 78 (50.6%) of 154 various primary tumors compared to adjacent normal tissue, including breast cancer (114480), lung cancer (211980), and gastric cancer (137215), among many others. Some tumors showed decreased expression of neighboring genes in addition to UTRN, suggesting deletions of chromosome 6q. Li et al. (2007) identified multiple somatic truncating mutations in the UTRN gene in primary breast cancers, neuroblastomas (256700), and melanomas (155600). Finally, overexpression of wildtype UTRN in breast cancer cells inhibited tumor cell growth in vitro and reduced their tumor potential in nude mice. Li et al. (2007) postulated that the tumor suppression function of UTRN may involve its function in maintaining normal cytoskeletal organization and cell membrane integrity.
Tinsley et al. (1992) found extensive homology between DRP and dystrophin over their entire length, suggesting that they derive from a common ancestral gene.
Based on similarities between genomic structures, Pearce et al. (1993) suggested that utrophin and dystrophin arose through an ancient duplication event involving a large region of genomic DNA.
Blake et al. (1992) proposed that the large product of the DMDL locus be called 'utrophin' since it is ubiquitously expressed. Alternative transcripts in this case might, they suggested, be referred to as apo-utrophin-1, apo-utrophin-2, etc.
Roberts et al. (1996) described a new dystrophin-related protein they called DRP2 (300052) and suggested that utrophin/DRP be renamed DRP1 to simplify future nomenclature.
Whereas absence of dystrophin at the muscle membrane leads to Duchenne muscular dystrophy in the human, dystrophin-deficient mdx mice appear physically normal despite their underlying muscle pathology. Deconinck et al. (1997) found that double-mutant mice deficient for both dystrophin and utrophin showed many signs typical of DMD in humans, including severe progressive muscular dystrophy resulting in premature death, ultrastructural neuromuscular and myotendinous junction abnormalities, and aberrantly coexpressed myosin heavy chain isoforms within the fiber. The data suggested that utrophin and dystrophin have complementing roles in normal functional or developmental pathways in muscle.
Grady et al. (1997) noted that utrophin is confined to the postsynaptic membrane at skeletal neuromuscular junctions and has been implicated in synaptic development. However, mice lacking utrophin show only subtle neuromuscular defects. Double-mutant mice with Dmd and Dmdl deficiency showed normal synaptic development, but muscular dystrophy was severe and closely resembled that seen in DMD. Grady et al. (1997) concluded that utrophin may attenuate the effects of dystrophin deficiency in mice.
To identify potential nonmechanical roles of dystrophin, Rafael et al. (2000) tested the ability of various truncated dystrophin transgenes to prevent any of the skeletal muscle abnormalities associated with the double knockout mouse deficient for both dystrophin and utrophin. Restoration of the dystrophin-associated protein complex (DAPC) with Dp71 did not prevent the structural abnormalities of the postsynaptic membrane or the abnormal oxidative properties of utrophin/dystrophin-deficient muscle. In contrast, a dystrophin protein lacking the cysteine-rich domain, which is unable to prevent dystrophy in the mdx mouse, was able to ameliorate these abnormalities in utrophin/dystrophin-deficient mice. The authors concluded that in addition to a mechanical role, dystrophin and utrophin are able to alter both structural and biochemical properties of skeletal muscle.
Blake, D. J., Love, D. R., Tinsley, J., Morris, G. E., Turley, H., Gatter, K., Dickson, G., Edwards, Y. H., Davies, K. E. Characterization of a 4.8kb transcript from the Duchenne muscular dystrophy locus expressed in schwannoma cells. Hum. Molec. Genet. 1: 103-109, 1992. [PubMed: 1301145] [Full Text: https://doi.org/10.1093/hmg/1.2.103]
Blake, D. J., Schofield, J. N., Zuellig, R. A., Gorecki, D. C., Phelps, S. R., Barnard, E. A., Edwards, Y. H., Davies, K. E. G-utrophin, the autosomal homologue of dystrophin Dp116, is expressed in sensory ganglia and brain. Proc. Nat. Acad. Sci. 92: 3697-3701, 1995. [PubMed: 7731967] [Full Text: https://doi.org/10.1073/pnas.92.9.3697]
Buckle, V. J., Guenet, J. L., Simon-Chazottes, D., Love, D. R., Davies, K. E. Localisation of a dystrophin-related autosomal gene to 6q24 in man, and to mouse chromosome 10 in the region of the dystrophia muscularis (dy) locus. Hum. Genet. 85: 324-326, 1990. [PubMed: 2203673] [Full Text: https://doi.org/10.1007/BF00206755]
Burton, E. A., Tinsley, J. M., Holzfeind, P. J., Rodrigues, N. R., Davies, K. E. A second promoter provides an alternative target for therapeutic up-regulation of utrophin in Duchenne muscular dystrophy. Proc. Nat. Acad. Sci. 96: 14025-14030, 1999. [PubMed: 10570192] [Full Text: https://doi.org/10.1073/pnas.96.24.14025]
Deconinck, A. E., Rafael, J. A., Skinner, J. A., Brown, S. C., Potter, A. C., Metzinger, L., Watt, D. J., Dickson, J. G., Tinsley, J. M., Davies, K. E. Utrophin-dystrophin-deficient mice as a model for Duchenne muscular dystrophy. Cell 90: 717-727, 1997. [PubMed: 9288751] [Full Text: https://doi.org/10.1016/s0092-8674(00)80532-2]
Grady, R. M., Teng, H., Nichol, M. C., Cunningham, J. C., Wilkinson, R. S., Sanes, J. R. Skeletal and cardiac myopathies in mice lacking utrophin and dystrophin: a model for Duchenne muscular dystrophy. Cell 90: 729-738, 1997. [PubMed: 9288752] [Full Text: https://doi.org/10.1016/s0092-8674(00)80533-4]
Guo, W.-X. A., Nichol, M., Merlie, J. P. Cloning and expression of full length mouse utrophin: the differential association of utrophin and dystrophin with AChR clusters. FEBS Lett. 398: 259-264, 1996. [PubMed: 8977119] [Full Text: https://doi.org/10.1016/s0014-5793(96)01216-1]
Hilton-Jones, D., Squier, M. V. Muscular dystrophy--dystrophin-associated protein complex: clinical implications. Lancet 341: 528-529, 1993. [PubMed: 8094778] [Full Text: https://doi.org/10.1016/0140-6736(93)90285-o]
Li, Y., Huang, J., Zhao, Y.-L., He, J., Wang, W., Davies, K. E., Nose, V., Xiao, S. UTRN on chromosome 6q24 is mutated in multiple tumors. Oncogene 26: 6220-6228, 2007. [PubMed: 17384672] [Full Text: https://doi.org/10.1038/sj.onc.1210432]
Love, D. R., Hill, D. F., Dickson, G., Spurr, N. K., Byth, B. C., Marsden, R. F., Walsh, F. S., Edwards, Y. H., Davies, K. E. An autosomal transcript in skeletal muscle with homology to dystrophin. Nature 339: 55-58, 1989. [PubMed: 2541343] [Full Text: https://doi.org/10.1038/339055a0]
Love, D. R., Morris, G. E., Ellis, J. M., Fairbrother, U., Marsden, R. F., Bloomfield, J. F., Edwards, Y. H., Slater, C. P., Parry, D. J., Davies, K. E. Tissue distribution of the dystrophin-related gene product and expression in the mdx and dy mouse. Proc. Nat. Acad. Sci. 88: 3243-3247, 1991. [PubMed: 2014247] [Full Text: https://doi.org/10.1073/pnas.88.8.3243]
Matsumura, K., Ervasti, J. M., Ohlendieck, K., Kahl, S. D., Campbell, K. P. Association of dystrophin-related protein with dystrophin-associated proteins in mdx mouse muscle. Nature 360: 588-591, 1992. [PubMed: 1461282] [Full Text: https://doi.org/10.1038/360588a0]
Pearce, M., Blake, D. J., Tinsley, J. M., Byth, B. C., Campbell, L., Monaco, A. P., Davies, K. E. The utrophin and dystrophin genes share similarities in genomic structure. Hum. Molec. Genet. 2: 1765-1772, 1993. [PubMed: 8281135] [Full Text: https://doi.org/10.1093/hmg/2.11.1765]
Prochniewicz, E., Henderson, D., Ervasti, J. M., Thomas, D. D. Dystrophin and utrophin have distinct effects on the structural dynamics of actin. Proc. Nat. Acad. Sci. 106: 7822-7827, 2009. [PubMed: 19416869] [Full Text: https://doi.org/10.1073/pnas.0812007106]
Rafael, J. A., Townsend, E. R., Squire, S. E., Potter, A. C., Chamberlain, J. S., Davies, K. E. Dystrophin and utrophin influence fiber type composition and post-synaptic membrane structure. Hum. Molec. Genet. 9: 1357-1367, 2000. [PubMed: 10814717] [Full Text: https://doi.org/10.1093/hmg/9.9.1357]
Roberts, R. G., Freeman, T. C., Kendall, E., Vetrie, D. L. P., Dixon, A. K., Shaw-Smith, C., Bone, Q., Bobrow, M. Characterization of DRP2, a novel human dystrophin homologue. Nature Genet. 13: 223-226, 1996. [PubMed: 8640231] [Full Text: https://doi.org/10.1038/ng0696-223]
Tinsley, J. M., Blake, D. J., Roche, A., Fairbrother, U., Riss, J., Byth, B. C., Knight, A. E., Kendrick-Jones, J., Suthers, G. K., Love, D. R., Edwards, Y. H., Davies, K. E. Primary structure of dystrophin-related protein. Nature 360: 591-593, 1992. [PubMed: 1461283] [Full Text: https://doi.org/10.1038/360591a0]
Wilson, J., Putt, W., Jimenez, C., Edwards, Y. H. Up71 and Up140, two novel transcripts of utrophin that are homologues of short forms of dystrophin. Hum. Molec. Genet. 8: 1271-1278, 1999. [PubMed: 10369873] [Full Text: https://doi.org/10.1093/hmg/8.7.1271]