Alternative titles; symbols
HGNC Approved Gene Symbol: DPYSL3
Cytogenetic location: 5q32 Genomic coordinates (GRCh38): 5:147,390,808-147,510,068 (from NCBI)
Byk et al. (1996) isolated and characterized a novel mouse phosphoprotein with significant homology to Unc33, a protein important for neuritic outgrowth and guidance in C. elegans. The cDNA isolated from mouse brain has an open reading frame that encodes a protein of 570 amino acids with a predicted molecular mass of 61,940 Da and a theoretical pI of 6.3. This sequence shows consensus sites for several protein kinases, corroborating biochemical studies indicating the phosphorylation of partially purified ULIP with protein kinase A (PKA; see 188830), casein kinase-2 (see 600505), and CDC2 kinase (116940). ULIP was found to be cytoplasmic in PC12 cells, and it exclusively associated with neurons, particularly at neuromuscular junctions. Byk et al. (1996) stated that 3 human ESTs show between 76 and 96% overall identity to the mouse ULIP sequence.
Hamajima et al. (1996) isolated a cDNA encoding dihydropyrimidinase-like 3 (DPYSL3), which they called DRP3, from a fetal brain cDNA library. By Northern blot analysis of adult human tissues, they detected a 5.8-kb DPYSL3 transcript at high levels in heart and skeletal muscle and at low levels in brain and lung.
Gaetano et al. (1997) isolated a human ULIP cDNA from retinoic acid-differentiated neuroblastoma cells. In contrast to Hamajima et al. (1996), they found that the gene is expressed strongly in human fetal brain and spinal cord but is not detectably expressed in adult brain and nonneuronal tissues. The 5.5-kb full-length cDNA contains a 1,710-bp open reading frame predicting a 570-amino acid protein. The human gene shares 98% identity with mouse Ulip. The authors speculated that the human ULIP gene mediates signals involved in axonal growth.
Matsuo et al. (2000) isolated the ULIP gene from a human leukocyte genomic library. By genomic sequence analysis, they determined that the 62-kD protein encoded by the ULIP gene has no signal sequence, transmembrane region, or protein-protein interaction domains. Northern blot analysis detected ULIP expression predominantly in heart and skeletal muscle but also in brain, pancreas, kidney, liver, and placenta. Neuroblastoma cells expressed 2-fold higher levels of ULIP than did myoblasts. Myoblast differentiation to myotubes resulted in downregulation of ULIP expression to undetectable levels. Retinoic acid-induced differentiation of neuroblastoma cells caused a 2.5-fold increase in ULIP expression.
Matsuo et al. (2000) determined that the ULIP gene contains 14 exons and a TATA-less promoter.
By FISH, Matsuo et al. (2000) mapped the ULIP gene to chromosome 5q32.
Due to its role in neurite and axonal outgrowth, Blasco et al. (2013) analyzed the DPYSL3 gene in patients with amyotrophic lateral sclerosis (ALS; 105400). A heterozygous A-to-G transition, resulting in an I141V substitution in the CRMP4a isoform and an I255V substitution in the CRMP4b isoform (rs147541241), was found in 2 of 183 French patients with familial ALS and in 5 of 285 French patients with sporadic ALS (overall frequency of 1.5%), but in none of 394 French controls. It was not possible to assess segregation of the variant. One of the French patients with familial disease also carried a hexanucleotide repeat expansion in the C9ORF72 gene (614260.0001), known to cause ALS (105550). The G allele of rs147541241 was found in 0.50% of large exome databases; based on the controls from these databases, the odds ratio of ALS patients carrying the mutation was 2.99. Subsequent examination of this variant in a Swedish population did not confirm the association: it was found in 2 of 184 patients with sporadic ALS and in 1 of 186 controls. One of the Swedish ALS patients with the variant also carried a C9ORF72 expansion mutation. In vitro functional expression studies in motor neuron cell cultures showed that the DPYSL3 variant reduced axonal growth and accelerated cell death compared to overexpression of the wildtype protein. Blasco et al. (2013) suggested that the identified variant may shorten motor neuron survival through a detrimental effect on axonal growth, and that this protein could act as a key unifier in transduction pathways leading to neurodegeneration through effects on early axon development.
Blasco, H., Bernard-Marissal, N., Vourc'h, P., Guettard, Y. O., Sunyach, C., Augereau, O., Khederchah, J., Mouzat, K., Antar, C., Gordon, P. H., Veyrat-Durebex, C., Besson, G., Andersen, P. M., Salachas, F., Meininger, V., Camu, W., Pettmann, B., Andres, C. R., Corcia, P., the French ALS Study Group. A rare motor neuron deleterious missense mutation in the DPYSL3 (CRMP4) gene is associated with ALS. Hum. Mutat. 34: 953-960, 2013. [PubMed: 23568759] [Full Text: https://doi.org/10.1002/humu.22329]
Byk, T., Dobransky, T., Cifuentes-Diaz, C., Sobel, A. Identification and molecular characterization of Unc-33-like phosphoprotein (Ulip), a putative mammalian homolog of the axonal guidance-associated unc-33 gene product. J. Neurosci. 16: 688-701, 1996. [PubMed: 8551352] [Full Text: https://doi.org/10.1523/JNEUROSCI.16-02-00688.1996]
Gaetano, C, Matsuo, T., Thiele, C. J. Identification and characterization of a retinoic acid-regulated human homologue of the unc-33-like phosphoprotein gene (hUlip) from neuroblastoma cells. J. Biol. Chem. 272: 12195-12201, 1997. [PubMed: 9115293] [Full Text: https://doi.org/10.1074/jbc.272.18.12195]
Hamajima, N., Matsuda, K., Sakata, S., Tamaki, N., Sasaki, M., Nonaka, M. A novel gene family defined by human dihydropyrimidinase and three related proteins with differential tissue distribution. Gene 180: 157-163, 1996. [PubMed: 8973361] [Full Text: https://doi.org/10.1016/s0378-1119(96)00445-3]
Matsuo, T., Stauffer, J. K., Walker, R. L., Meltzer, P., Thiele, C. J. Structure and promoter analysis of the human unc-33-like phosphoprotein gene: E-box required for maximal expression in neuroblastoma and myoblasts. J. Biol. Chem. 275: 16560-16568, 2000. Note: Erratum: J. Biol. Chem. 275: 25052-25053, 2000. [PubMed: 10748015] [Full Text: https://doi.org/10.1074/jbc.M001312200]