Alternative titles; symbols
HGNC Approved Gene Symbol: MACF1
Cytogenetic location: 1p34.3 Genomic coordinates (GRCh38) : 1:39,084,167-39,487,138 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p34.3 | Lissencephaly 9 with complex brainstem malformation | 618325 | Autosomal dominant | 3 |
ACF7 is a member of the spectraplakin family of cytoskeletal cross-linking proteins that possess actin- and microtubule-binding domains (Kodama et al., 2003).
By sequencing clones obtained from a size-fractionated adult brain cDNA library, Nagase et al. (1999) cloned MACF1, which they designated KIAA1251. The 3-prime UTR of the transcript contains Alu repeat sequences, and the deduced protein contains 1,483 amino acids. RT-PCR ELISA detected low expression of MACF1 in lung, ovary, and liver.
Sun et al. (1999) cloned several contiguous partial MACF1 cDNAs from a prostate cDNA library and assembled the full-length sequence. The deduced 5,373-amino acid MACF1 protein, which they designated trabeculin-alpha, has a calculated molecular mass of 614 kD. MACF1 has an N-terminal actin-binding domain, followed by a plectin (601282)-like domain, 29 central spectrin (see 182860)-like repeats, and a C-terminal region that contain 2 tandem Ca(2+)-binding EF-hand motifs, a GAR22 (GAS2L1; 602128)-like domain, and a serine-rich region. The C terminus also has several putative tyrosine kinase motifs. MACF1 shares 88% amino acid with its mouse homolog. Northern blot analysis detected MACF1 expression in all tissues examined, with highest expression in heart, skeletal muscle, prostate, intestine, colon, and gonads. Lowest expression was in brain, spleen, thymus, liver, placenta, and lung. Immunofluorescence analysis of several cell lines detected MACF1 distributed in a filamentous network throughout the cytoplasm, with exclusion from the nucleus.
By PCR of the HepG2 hepatoma cell line with degenerate primers based on conserved C-terminal domains of FAK (600758) and CAKB (601212), followed by screening a HepG2 cell line cDNA library, Okuda et al. (1999) cloned MACF1, which they designated macrophin. The deduced 5,430-amino acid protein has a calculated molecular mass of 620 kD. RT-PCR detected high expression in heart, placenta, liver, kidney, and pancreas, moderate expression in brain and lung, and weak expression in skeletal muscle. In situ hybridization of pancreas showed mRNA mainly in acinar tissue.
By searching sequence databases using a chicken partial cDNA that was differentially expressed during regeneration of the auditory epithelium after noise trauma, followed by screening pituitary gland and heart cDNA libraries, Gong et al. (2001) cloned a splice variant of MACF1. The deduced protein, which they called MACF1-4, has a calculated molecular mass of 670 kD, contains 8 N-terminal plectin repeats, and has no actin-binding domain. The authors noted that 3 other splice variants with different N termini had been identified for mouse Macf1. mRNA dot blot analysis showed that MACF1 was expressed ubiquitously, with highest expression in pituitary, adrenal, thyroid, salivary gland, mammary gland, pancreas, heart, and skeletal muscle. mRNA dot blot analysis using a riboprobe specific for the MACF1-4 variant showed highest expression in heart, lung, pituitary gland, and placenta. PCR analysis using MACF1-4-specific primers detected MACF1-4 in lung, heart, pituitary, and placenta, but not in brain, kidney, liver, pancreas, skeletal muscle, or HepG2 hepatoma cells.
May-Simera et al. (2016) found that mouse Macf1 was concentrated at the apical domain of the neuroblast layer and in the inner plexiform layer during early postnatal development of the retina. As the retina matured, Macf1 localization was enriched in the plexiform layers and at the apical edge of the outer nuclear layer. In the adult retina, Macf1 colocalized with the basal body beneath the photoreceptor connecting cilium.
By sedimentation binding assay, Sun et al. (1999) confirmed that the N-terminal actin-binding domain of MACF1 coprecipitated with F-actin. Cytochalasin D disruption of actin filaments also resulted in a marked but incomplete disruption of MACF1 fine filament structures and the appearance of punctate aggregates of MACF1. Mouse Macf1 mRNA levels increased steadily during formation of fused myotubes during differentiation in a mouse myoblasts cell line.
Kodama et al. (2003) showed that mouse Acf7 is an essential integrator of microtubule-actin dynamics. In mouse endodermal cells, Acf7 bound along microtubules, but concentrated at their distal ends and at cell borders when polarized. In the absence of Acf7, microtubules still bound Eb1 (603108) and Clip170 (179838), but they no longer grew along polarized actin bundles, nor did they pause and tether to actin-rich cortical sites. The consequences were long, less stable microtubules with skewed cytoplasmic trajectories and altered dynamic instability. In response to wounding, Acf7 null cultures activated polarizing signals, but they failed to maintain them and coordinate migration. Rescue of these defects required the actin- and microtubule-binding domains of Acf7. Kodama et al. (2003) concluded that spectraplakins are important for controlling microtubule dynamics and reinforcing links between microtubules and polarized F-actin, so that cellular polarization and coordinated cell movements can be sustained.
Chen et al. (2006) found that siRNA knockdown of Macf1 inhibited Wnt signaling (see WNT1, 164820) in a mouse embryonic carcinoma cell line. Reporter gene assays indicated that Macf1 acted upstream of Gsk3b (605004) in the Wnt signaling pathway. Macf1 interacted directly with Axin (see AXIN1, 603816) and translocated with the Axin complex to the cell membrane upon Wnt stimulation.
A resident population of adult stem cells (SCs) in hair follicles is involved in hair growth and in epidermal reepithelialization during wound healing. Wu et al. (2011) found that adult mouse hair follicle SCs expressed high levels of Acf7 and that phosphorylation of Acf7 by Gsk3-beta reduced the affinity of Acf7 for microtubules. Expression of a constitutively active Gsk3-beta mutant in hair follicle SCs resulted in elevated phosphorylation of Acf7 and altered microtubule structure similar to that in Acf7-knockout cells. Conversely, inhibition of Gsk3-beta increased microtubule binding by endogenous Acf7 in hair follicle SCs. SC migration in a wound-healing assay was inhibited by Acf7 knockout and by both over- and underactivation of Gsk3-beta. Wu et al. (2011) concluded that cyclic phosphorylation of Acf7 by Gsk3-beta is required for Acf7- and microtubule-based cell migration in hair follicle SCs.
May-Simera et al. (2016) found that deletion of Macf1 in mice caused disrupted retinal lamination and arrested photoreceptor maturation. Failed ciliogenesis caused disruption of the polarity of developing photoreceptors was disrupted in the retina. Macf1 was also found to be required for the basal body positioning in mature photoreceptors. Pull-down assays demonstrated that Macf1 interacts with ciliary and basal body proteins. Examination of mutant mouse embryonic fibroblasts revealed that Macf1 promoted anchoring of microtubules to the mother centriole, and that loss of Macf1 resulted in the changes in the cellular transcriptome and proteome.
Ka and Kim (2016) found that deletion of mouse Macf1 in developing pyramidal neurons caused defects in normal dendrite differentiation in cortical and hippocampal neurons. Macf1 deletion also affected dendritic spine formation in cortical pyramidal neurons and suppressed the axonal growth and branching in projection neurons. Macf1 controlled neurite growth and branching by regulating the arrangement and stabilization of actin and microtubules and mediating GSK3 signaling.
Gong et al. (2001) determined that the MACF1 gene contains at least 102 exons and spans more than 270 kb.
By radiation hybrid analysis, Nagase et al. (1999) mapped the MACF1 gene to chromosome 1. Okuda et al. (1999) mapped the MACF1 gene to chromosome 1p32-p31 by radiation hybrid analysis and genomic sequence analysis. By FISH, Sun et al. (1999) mapped the MACF1 gene to chromosome 1p34.2-p33.
Gong et al. (2001) mapped the mouse Macf1 gene to a region of mouse chromosome 4 that shows homology of synteny to human chromosome 1p32.
In 9 patients, including a pair of monozygotic twin sisters, with lissencephaly-9 with complex brainstem malformation (LIS9; 618325), Dobyns et al. (2018) identified de novo heterozygous mutations in the MACF1 gene (608271.0001-608271.0006). The patients were unrelated, except for the twin sisters, and were ascertained from several clinical or research centers. The mutations were identified by whole-exome or whole-genome sequencing. There were 5 missense mutations and 1 intragenic deletion. Four of the missense mutations found in 7 patients occurred at highly conserved zinc-binding residues in or near the GAR domain, all of which were predicted by molecular modeling to alter the configuration of the domain and likely abrogate microtubule binding. One patient had a missense mutation in the spectrin repeat domain (G4706R; 608271.0006); the authors noted that this patient had only subtle brainstem dysplasia compared to patients with mutations in the GAR domain. Cells derived from 2 patients showed an increased number of shortened cilia compared to wildtype. Otherwise, functional studies of the variants and studies of patient cells were not performed. Dobyns et al. (2018) noted that Macf1-null mice have been shown to have disrupted neuronal migration via disruption of microtubule dynamics, including abnormal axonal extension and guidance with defects in midline crossing.
Chen et al. (2006) found that Macf1 -/- mice died at the gastrulation stage and displayed developmental retardation at embryonic day 7.5 with defects in the formation of the primitive streak, node, and mesoderm. The phenotype was similar to that of Wnt3 (165330)-null mice and Lrp5 (603506)/Lrp6 (603507) double-knockout mice.
In 2 unrelated patients (LR14-088 and LR17-434) with lissencephaly-9 with complex brainstem malformation (LIS9; 618325), Dobyns et al. (2018) identified a de novo heterozygous c.15530G-T transversion (c.15530G-T, NM_012090.5) in the MACF1 gene, resulting in a cys5177-to-phe (C5177F) substitution at a highly conserved zinc-binding residue in the GAR domain. The mutation, which was found by trio-based exome sequencing, was not found in the gnomAD database.
In 2 unrelated patients (LR16-306 and LR17-450) with lissencephaly-9 with complex brainstem malformation (LIS9; 618325), Dobyns et al. (2018) identified a de novo heterozygous c.15682G-T transversion (c.15682G-T, NM_012090.5) in the MACF1 gene, resulting in an asp5228-to-tyr (D5228Y) substitution at a highly conserved zinc-binding residue in the GAR domain. The mutation, which was found by trio-based exome sequencing, was not found in the gnomAD database.
In a patient (LR18-077) with lissencephaly-9 with complex brainstem malformation (LIS9; 618325), Dobyns et al. (2018) identified a de novo heterozygous c.15688T-G transversion (c.15688T-G, NM_12090.5) in the MACF1 gene, resulting in a cys5230-to-gly (C5230G) substitution at a highly conserved zinc-binding residue in the GAR domain. The mutation, which was found by trio-based exome sequencing, was not found in the gnomAD database.
In a set of monozygotic twin sisters (LR04-67 a1 and a2) with lissencephaly-9 with complex brainstem malformation (LIS9; 618325), Dobyns et al. (2018) identified a de novo heterozygous c.15689G-T transversion (c.15689G-T, NM_012090.5) in the MACF1 gene, resulting in a cys5230-to-phe (C5230F) substitution at a highly conserved zinc-binding residue in the GAR domain. The mutation, which was found by trio-based exome sequencing, was not found in the gnomAD database.
In a Japanese girl (LR18-070), previously reported by Irahara et al. (2014), with lissencephaly-9 with complex brainstem malformation (LIS9; 618325), Dobyns et al. (2018) identified a de novo heterozygous intragenic 39.6-kb deletion (c.10617+444_15577-288del, NM_012090.5) in the MACF1 gene, resulting in the deletion of exons 58 and 59 (Ala3540_Arg5192del), predicted to remove several functional domain. The deletion was found by exome and genome sequencing and confirmed by PCR analysis of patient cells. It was not found in the gnomAD database.
In a patient (LR16-412) with lissencephaly-9 with complex brainstem malformation (LIS9; 618325), Dobyns et al. (2018) identified a de novo heterozygous c.14116G-C transversion (c.14116G-C, NM_012090.5) in the MACF1 gene, resulting in a gly4706-to-arg (G4706R) substitution at a conserved residue in the spectrin repeat domain. The mutation, which was found by exome sequencing, was not present in the gnomAD database. The authors noted that this patient had only subtle brainstem dysplasia compared to patients with mutations in the GAR domain.
Chen, H.-J., Lin, C.-M., Lin, C.-S., Perez-Olle, R., Leung, C. L., Liem, R. K. H. The role of microtubule actin cross-linking factor 1 (MACF1) in the Wnt signaling pathway. Genes Dev. 20: 1933-1945, 2006. [PubMed: 16815997] [Full Text: https://doi.org/10.1101/gad.1411206]
Dobyns, W. B., Aldinger, K. A., Ishak, G. E., Mirzaa, G. M., Timms, A. E., Grout, M. E., Dremmen, M. H. G., Schot, R., Vandervore, L., van Slegtenhorst, M. A., Wilke, M., Kasteleijn, E., and 23 others. MACF1 mutations encoding highly conserved zinc-binding residues of the GAR domain cause defects in neuronal migration and axon guidance. Am. J. Hum. Genet. 103: 1009-1021, 2018. [PubMed: 30471716] [Full Text: https://doi.org/10.1016/j.ajhg.2018.10.019]
Gong, T.-W. L., Besirli, C. G., Lomax, M. I. MACF1 gene structure: a hybrid of plectin and dystrophin. Mammalian Genome 12: 852-861, 2001. [PubMed: 11845288] [Full Text: https://doi.org/10.1007/s00335-001-3037-3]
Irahara, K., Saito, Y., Sugai, K., Nakagawa, E., Saito, T., Komaki, H., Nakata, Y., Sato, N., Baba, K., Yamamoto, T., Chan, W.-M., Andrews, C., Engle, E. C., Sasaki, M. Pontine malformation, undecussated pyramidal tracts, and regional polymicrogyria: a new syndrome. Pediat. Neurol. 50: 384-388, 2014. [PubMed: 24507697] [Full Text: https://doi.org/10.1016/j.pediatrneurol.2013.12.013]
Ka, M., Kim, W.-Y. Microtubule-actin crosslinking factor 1 is required for dendritic arborization and axon outgrowth in the developing brain. Molec. Neurobiol. 53: 6018-6032, 2016. [PubMed: 26526844] [Full Text: https://doi.org/10.1007/s12035-015-9508-4]
Kodama, A., Karakesisoglou, I., Wong, E., Vaezi, A., Fuchs, E. ACF7: an essential integrator of microtubule dynamics. Cell 115: 343-354, 2003. [PubMed: 14636561] [Full Text: https://doi.org/10.1016/s0092-8674(03)00813-4]
May-Simera, H. L., Gumerson, J. D., Gao, C., Campos, M., Cologna, S. M., Beyer, T., Boldt, K., Kaya, K. D., Patel, N., Kretschmer, F., Kelley, M. S., Petralia, R. S., Davey, M. G., Li, T. Loss of MACF1 abolishes ciliogenesis and disrupts apicobasal polarity establishment in the retina. Cell Rep. 17: 1399-1413, 2016. [PubMed: 27783952] [Full Text: https://doi.org/10.1016/j.celrep.2016.09.089]
Nagase, T., Ishikawa, K., Kikuno, R., Hirosawa, M., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. XV. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 6: 337-345, 1999. [PubMed: 10574462] [Full Text: https://doi.org/10.1093/dnares/6.5.337]
Okuda, T., Matsuda, S., Nakatsugawa, S., Ichigotani, Y., Iwahashi, N., Takahashi, M., Ishigaki, T., Hamaguchi, M. Molecular cloning of macrophin, a human homologue of Drosophila kakapo with a close structural similarity to plectin and dystrophin. Biochem. Biophys. Res. Commun. 264: 568-574, 1999. [PubMed: 10529403] [Full Text: https://doi.org/10.1006/bbrc.1999.1538]
Sun, Y., Zhang, J., Kraeft, S.-K., Auclair, D., Chang, M.-S., Liu, Y., Sutherland, R., Salgia, R., Griffin, J. D., Ferland, L. H., Chen, L. B. Molecular cloning and characterization of human trabeculin-alpha, a giant protein defining a new family of actin-binding proteins. J. Biol. Chem. 274: 33522-33530, 1999. [PubMed: 10559237] [Full Text: https://doi.org/10.1074/jbc.274.47.33522]
Wu, X., Shen, Q.-T., Oristian, D. S., Lu, C. P., Zheng, Q., Wang, H.-W., Fuchs, E. Skin stem cells orchestrate directional migration by regulating microtubule-ACF7 connections through GSK3-beta. Cell 144: 341-352, 2011. [PubMed: 21295697] [Full Text: https://doi.org/10.1016/j.cell.2010.12.033]