HGNC Approved Gene Symbol: MAP4
Cytogenetic location: 3p21.31 Genomic coordinates (GRCh38): 3:47,850,695-48,088,848 (from NCBI)
MAP4 is a major protein for microtubule assembly during mitosis (summary by Zahnleiter et al., 2015).
Chapin and Bulinski (1991) used a polyclonal antiserum raised against a HeLa cell microtubule-associated protein of M(r) 210,000 (210-kD MAP or MAP4), an abundant nonneuronal MAP, to isolate cDNA clones from a human fetal brain lambda gt11 cDNA expression library. They found that this, the major human nonneuronal MAP, resembles 2 neuronal MAPs in its microtubule-binding domain, while most of the molecule has sequences, and presumably functions, distinct from those of the neuronal MAPs (e.g., 157130).
West et al. (1991) reported the protein structure of MAP4 on the basis of comparisons of the human, mouse, and bovine sequences.
Chapin et al. (1995) isolated clones encoding alternatively spliced forms of MAP4. One isoform is similar to an isoform of tau (157140) in structure.
Chapin et al. (1995) mapped the MAP4 gene to chromosome 3p21 by fluorescence in situ hybridization. Mangan and Olmsted (1996) demonstrated that the murine homolog is located on mouse chromosome 9.
For discussion of a possible association between mutation in the MAP4 gene and severe short stature with normocephaly, see 157132.0001.
This variant is classified as a variant of unknown significance because its contribution to severe short stature and normocephaly has not been confirmed.
In 2 children with severe growth retardation and normocephaly and without signs of skeletal dysplasia, who were born to consanguineous parents of Macedonian origin, Zahnleiter et al. (2015) identified homozygosity for a MAP4 variant, c.1117G-A transition (c.1117G-A, NM_002375.4) in exon 7 of the MAP4 gene, resulting in an ala391-to-thr (A391T) substitution. The mutation was found by a combination of homozygosity mapping and next-generation sequencing and was confirmed by Sanger sequencing. Patient 1 had prenatal growth retardation, microcephaly at birth that progressed to relative macrocephaly, minor learning disabilities, scoliosis, broad thorax, brachydactyly, short and wide feet, small long face, high prominent forehead, and broad nose tip. Patient 2 had prenatal growth retardation, microcephaly at a young age that progressed to relative macrocephaly, long face, high prominent forehead, and broad nose tip. Both patients had cone-shaped epiphyses of phalanges 3 and 4 and fused carpal bones. Quantitative real-time RT-PCR and Western blot analysis suggested a loss-of-function effect of the variant. In functional studies, Zahnleiter et al. (2015) found centrosome amplifications in mitotic fibroblast cells in vivo and in vitro. These numeric centrosomal aberrations were also present during interphase, resulting in aberrant ciliogenesis. Affected cells showed a dysfunction of the microtubule-dependent assembly of the Golgi apparatus, indicated by a significant lack of compactness of Golgi membranes. Zahnleiter et al. (2015) screened the MAP4 gene in 278 additional patients with severe short stature and microcephaly, but identified no pathogenic variants.
Chapin, S. J., Bulinski, J. C. Non-neuronal 210 x 10(3) M(r) microtubule-associated protein (MAP4) contains a domain homologous to the microtubule-binding domains of neuronal MAP2 and tau. J. Cell Sci. 98: 27-36, 1991. [PubMed: 1905296] [Full Text: https://doi.org/10.1242/jcs.98.1.27]
Chapin, S. J., Lue, C.-M., Yu, M. T., Bulinski, J. C. Differential expression of alternatively spliced forms of MAP4: a repertoire of structurally different microtubule-binding domains. Biochemistry 34: 2289-2301, 1995. [PubMed: 7857940] [Full Text: https://doi.org/10.1021/bi00007a025]
Mangan, M. E., Olmsted, J. B. The gene for microtubule-associated protein 4 (Mtap4) maps to the distal region of mouse chromosome 9. Mammalian Genome 7: 918-925, 1996. [PubMed: 8995766] [Full Text: https://doi.org/10.1007/s003359900270]
West, R. R., Tenbarge, K. M., Olmsted, J. B. A model for microtubule-associated protein 4 structure: domains defined by comparisons of human, mouse, and bovine sequences. J. Biol. Chem. 266: 21886-21896, 1991. [PubMed: 1718985]
Zahnleiter, D., Hauer, N. N., Kessler, K., Uebe, S., Sugano, Y., Neuhauss, S. C. F., Giessl, A., Ekici, A. B., Blessing, H., Sticht, H., Dorr, H.-G., Reis, A., Thiel, C. T. MAP4-dependent regulation of microtubule formation affects centrosome, cilia, and Golgi architecture as a central mechanism in growth regulation. Hum. Mutat. 36: 87-97, 2015. [PubMed: 25323976] [Full Text: https://doi.org/10.1002/humu.22711]