Alternative titles; symbols
HGNC Approved Gene Symbol: MAP1B
Cytogenetic location: 5q13.2 Genomic coordinates (GRCh38): 5:72,107,475-72,209,565 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q13.2 | ?Deafness, autosomal dominant 83 | 619808 | Autosomal dominant | 3 |
| Periventricular nodular heterotopia 9 | 618918 | Autosomal dominant | 3 |
The MAP1B gene encodes a member of the microtubule binding family of proteins that are important for axonal growth and synapse maturation during brain development. MAP1B is primarily expressed in the neuronal soma, dendrites, and axons; it is enriched in the axonal growth cone during development. In the adult brain, MAP1B expression remains high in areas that retain plasticity. MAP1B undergoes post-translational modification in which it is cleaved into a heavy chain (HC) and a light chain (LC1) (summary by Walters et al., 2018).
Using a polyclonal antiserum directed against the C-terminal domain of dystrophin, Lien et al. (1991) isolated a cDNA clone encoding an antigenically cross-reactive protein, microtubule-associated protein-1B (MAP1B).
Lien et al. (1994) completely cloned and sequenced the human MAP1B gene. The deduced 830-amino acid protein showed 91% overall identity with rat and mouse MAP1B. MAP1B is expressed at high levels in brain and spinal cord and at much lower levels in muscle.
Cui et al. (2020) found high expression of the Map1b gene in mouse brain and various regions of the cochlea, including in spiral ganglion neurons, with lesser expression in hair cells.
Hammarback et al. (1991) found that LC1, one of the 3 light chains that makes up the MAP1B complex, is encoded within the 3-prime end of MAP1B. Their data suggested that the heavy chain and LC1 are produced by proteolytic processing of a precursor polypeptide.
Lien et al. (1994) determined that the MAP1B gene has 7 exons; the third exon contains sequence not represented in mouse or rat MAP1B. This sequence, labeled 3A, is present at the 5-prime end of an alternative transcript that is expressed at approximately one-tenth the level of the full-length transcript.
By in situ hybridization, Lien et al. (1991) mapped the MAP1B gene to chromosome 5q13 in proximity to the spinal muscular atrophy (SMA; 253300) locus. MAP1B was found to be the closest marker distal to the locus for SMA; its 5-prime end was oriented toward the centromere (Wirth et al., 1993).
Allen et al. (2005) showed that gigaxonin (605379) controls protein degradation and is essential for neuronal function and survival. They presented evidence that gigaxonin binds to the ubiquitin-activating enzyme E1 (314370) through its amino-terminal BTB domain, while the carboxy-terminal kelch repeat domain interacts directly with the light chain (LC) of MAP1B. Overexpression of gigaxonin led to enhanced degradation of MAP1B-LC, which could be antagonized by proteasome inhibitors. Ablation of gigaxonin caused a substantial accumulation of MAP1B-LC in giant axonal neuropathy (GAN)-null neurons. Moreover, Allen et al. (2005) showed that overexpression of MAP1B in wildtype cortical neurons led to cell death characteristic of GAN-null neurons, whereas reducing MAP1B levels significantly improved the survival rate of null neurons. Allen et al. (2005) concluded that their results identified gigaxonin as a ubiquitin scaffolding protein that controls MAP1B-LC degradation and provided insight into the molecular mechanisms underlying human neurodegenerative disorders.
Scales et al. (2009) found that Dyrk1a (600855) phosphorylated Map1b at S1392 to prime Map1b for subsequent phosphorylation by Gsk3-beta (GSK3B; 605004) at S1388 in cultured rat embryonic cortical neurons. Further analysis demonstrated that Dyrk1a-primed and nonprimed Gsk3-beta phosphorylation sites were involved in regulation of microtubule stability in growing cortical neuronal axons.
Periventricular Nodular Heterotopia 9
In 4 unrelated probands with periventricular nodular heterotopia-9 (PVNH9; 618918), Heinzen et al. (2018) identified heterozygous nonsense or frameshift mutations in the MAP1B gene (see, e.g., 157129.0001-157129.0003). One patient had a de novo mutation, 2 unrelated patients inherited the variants from clinically unaffected fathers who did not undergo brain imaging, and the last patient inherited the mutation from a mother who had similar, but milder, structural abnormalities on brain imaging. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were not found in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but all were predicted to cause premature termination and a loss of function (LOF). Heinzen et al. (2018) noted that while MAP1B is very intolerant to functional variation, LOF variants have rarely been observed in the ExAC and gnomAD databases. The patients were ascertained from a cohort of 202 individuals with PVNH who underwent exome sequencing.
In affected members of 3 Icelandic families with PVNH9, Walters et al. (2018) identified 3 different heterozygous nonsense or frameshift mutations in exon 5 of the MAP1B gene (157129.0004-157129.0006). The mutations, which were found by whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families, although there was variable expressivity of the phenotype. None of the variants were present in public databases, including gnomAD. Expression of the mutations into HeLa cells showed that truncated proteins of the expected size were produced. Walters et al. (2018) stated that all the mutations resulted in absence of the LC1 domain of the protein.
In a 7-year-old boy with PVNH9, Julca et al. (2019) identified a de novo heterozygous nonsense mutation in the MAP1B gene (E679X; 157129.0007). The mutation was found by whole-exome sequencing; functional studies of the variant and studies of patient cells were not performed.
Autosomal Dominant Deafness 83
In 7 affected members of a 3-generation Han Chinese family (NB066) with autosomal dominant deafness-83 (DFNA83; 619808), Cui et al. (2020) identified a heterozygous missense mutation in the MAP1B gene (S1400G; 157129.0008). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Otic sensory neuron (OSN)-like cells generated from patient-derived pluripotent stem cells carrying the mutation showed decreased mRNA and protein levels of MAP1B and decreased neurite outgrowth compared to control wildtype OSN-like cells and to patient cell lines in which the S1400G mutation had been corrected using CRISPR/Cas9 technology. There was also a slight decrease in type I phosphorylation of mutant MAP1B cells compared to controls, which contributed to a cell differentiation defect. Additional in vitro studies demonstrated that the S1400G mutation caused altered microtubule dynamics and increased acetylation of microtubules associated with impaired axonal elongation. Electrophysiologic studies of these mutant OSN-like cells showed that the S1400G mutation decreased spike amplitudes, prolonged spike width, increased spike latency, and raised the threshold of action potential activation compared to controls, consistent with impaired neuronal function. These alterations were restored by CRISPR/Cas9-mediated genetic correction of the MAP1B mutation in vitro. Cui et al. (2020) concluded that the hearing loss in these patients was caused by dysfunction of spiral ganglion neurons due to MAP1B deficiency. The patients had onset of slowly progressive sensorineural hearing loss at an average age of 24 years.
Neuronal microtubules are considered to have a role in dendrite and axon formation. Different portions of the developing and adult brain microtubules are associated with different microtubule-associated proteins. MAP1B is expressed in different portions of the brain and may have a role in neuronal plasticity and brain development. Edelmann et al. (1996) generated mice that carry an insertion in MAP1B by gene targeting methods. Mice homozygous for the modification died during embryogenesis. The heterozygotes exhibited a spectrum of phenotypes including slower growth rates, lack of visual acuity in one or both eyes, and motor system abnormalities. Histochemical analysis of the severely affected mice revealed that their Purkinje cell dendritic processes were abnormal, did not react with MAP1B antibodies, and showed reduced staining with MAP1A (600178) antibodies. Similar histologic and immunochemical changes were observed in the olfactory bulb, hippocampus, and retina, providing a basis for the observed phenotypes.
Zhang et al. (2001) developed a Drosophila model of fragile X syndrome (300624) using loss-of-function mutants and overexpression of the FMR1 (309550) homolog, Dfxr (Drosophila fragile X-related gene). Dfxr nulls displayed enlarged synaptic terminals, whereas neuronal overexpression resulted in fewer and larger synaptic boutons. Synaptic structural defects were accompanied by altered neurotransmission, with synapse type-specific regulation in central and peripheral synapses. These phenotypes mimicked those observed in mutants of Futsch, a microtubule-associated protein with homology to mammalian MAP1B. Immunoprecipitation of Dfxr showed association with Futsch mRNA, and Western blot analyses demonstrated that Dfxr inversely regulates Futsch expression. Dfxr-Futsch double mutants restored normal synaptic structure and function. Zhang et al. (2001) proposed that Dfxr acts as a translational repressor of Futsch to regulate microtubule-dependent synaptic growth and function.
Cui et al. (2020) found that Map1b-null mice died by 10 days after birth. Heterozygous Map1b+/- mice showed progressive hearing loss and higher auditory brainstem response (ABR) thresholds beginning at about 4 weeks of age. There was no evidence for morphologic or functional defects in hair cells or the organ of Corti. Although the spiral ganglion neuron density was similar to wildtype, they had decreased amount of Map1b, shortened neurite length, and abnormally increased acetylation of microtubules compared to controls. These findings were associated with deficient phosphorylation of Map1b. Electrophysiologic studies showed altered properties of the mutant spiral ganglion neurons, including decreased outward K+ currents, decreased peak current density, decreased spike amplitude and prolonged spike width, and raised threshold of action potential activation compared to wildtype. The findings demonstrated that Map1b deficiency alters the morphology and electrophysiology of spiral ganglion neurons in mice.
In a patient with periventricular nodular heterotopia-9 (PVNH9; 618918), Heinzen et al. (2018) identified a de novo heterozygous c.907C-T transition (c.907C-T, NM_005909.3) in exon 5 of the MAP1B gene, resulting in an arg303-to-ter (R303X) substitution. The mutation, which was found by trio-based exome sequencing and confirmed by Sanger sequencing, was not found in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to result in a loss of function.
In a patient with periventricular nodular heterotopia-9 (PVNH9; 618918), Heinzen et al. (2018) identified a heterozygous c.1594C-T transition (c.1594C-T, NM_005909.3) in exon 5 of the MAP1B gene, resulting in a gln532-to-ter (Q532X) substitution. The patient inherited the mutation from a clinically unaffected father who did not undergo brain imaging. The mutation, which was found by trio-based exome sequencing and confirmed by Sanger sequencing, was not found in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to result in a loss of function.
In a patient with periventricular nodular heterotopia-9 (PVNH9; 618918), Heinzen et al. (2018) identified a heterozygous c.3316C-T transition (c.3316C-T, NM_005909.3) in exon 5 of the MAP1B gene, resulting in an arg1106-to-ter (R1106X) substitution. The patient inherited the mutation from the mother, who had similar, but less severe, abnormalities on brain imaging. The mutation, which was found by trio-based exome sequencing and confirmed by Sanger sequencing, was not found in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to result in a loss of function.
In 8 affected members of a 5-generation Icelandic family (family 1) with periventricular nodular heterotopia-9 (PVNH9; 618918), Walters et al. (2018) identified a heterozygous 1-bp deletion (c.2133delG, NM_005909) in exon 5 of the MAP1B gene, resulting in a frameshift and premature termination (Glu712LysfsTer10) in the microtubule-binding domain of the heavy chain. The mutation, which was found by whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. However, 1 individual with a diagnosis of intellectual disability and an IQ of 57 did not carry the variant. The mutation was not found in public databases, including gnomAD, or in over 30,000 Icelandic individuals. Expression of the mutation into HeLa cells showed that a truncated protein of the expected size was produced.
In 3 Icelandic sibs and their mother (family 2) with variable expressivity of periventricular nodular heterotopia-9 (PVNH9; 618918), Walters et al. (2018) identified a heterozygous c.3094G-T transversion (c.3094G-T, NM_005909) in exon 5 of the MAP1B gene, resulting in a glu1032-to-ter (E1032X) substitution in the heavy chain region of the protein. The mutation, which was found by whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in public databases, including gnomAD. Expression of the mutation into HeLa cells showed that a truncated protein of the expected size was produced.
In a mother and daughter (family 3) with variable expressivity of periventricular nodular heterotopia-9 (PVNH9; 618918), Walters et al. (2018) identified a heterozygous c.4990C-T transition (c.4990C-T, NM_005909) in exon 5 of the MAP1B gene, resulting in an arg1664-to-ter (R1664X) substitution in the heavy chain region of the protein. The mutation, which was found by whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in public databases, including gnomAD. Expression of the mutation into HeLa cells showed that a truncated protein of the expected size was produced.
In a 7-year-old boy with periventricular nodular heterotopia-9 (PVNH9; 618918), Julca et al. (2019) identified a de novo heterozygous c.2035G-T transversion (c.2035G-T, NM_005909) in exon 5 of the MAP1B gene, resulting in a glu679-to-ter (E679X) substitution. The mutation was found by whole-exome sequencing; functional studies of the variant and studies of patient cells were not performed.
In 7 affected members of a 3-generation Han Chinese family (NB066) with autosomal dominant deafness-83 (DFNA83; 619808), Cui et al. (2020) identified a heterozygous c.4198A-G transition (c.4198A-G, NM_005909.4) in the MAP1B gene, resulting in a ser1400-to-gly (S1400G) substitution at a conserved residue in the microtubule assembly helping (MTA) domain, which is the highly conserved phosphorylation site critical for microtubule assembly. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation was present at a low frequency in the gnomAD database (6.8 x 10(-5), 17 of 250,672 alleles). Otic sensory neuron (OSN)-like cells generated from patient-derived pluripotent stem cells carrying the mutation showed decreased mRNA and protein levels of MAP1B and decreased neurite outgrowth compared to control wildtype OSN-like cells and to patient cell lines in which the S1400G mutation had been corrected using CRISPR/Cas9 technology. There was also a slight decrease in type I phosphorylation of mutant MAP1B cells compared to controls, which contributed to a neuronal differentiation defect. Additional in vitro studies demonstrated that the S1400G mutation caused altered microtubule dynamics and increased acetylation of microtubules associated with impaired axonal elongation. Electrophysiologic studies showed that the S1400G mutation decreased spike amplitudes, prolonged spike width, increased spike latency, and raised the threshold of action potential activation compared to controls, consistent with impaired neuronal function. These alterations were restored by CRISPR/Cas9-mediated genetic correction of the MAP1B mutation in vitro. The patients had onset of slowly progressive sensorineural hearing loss at an average age of 24 years.
Allen, E., Ding, J., Wang, W., Pramanik, S., Chou, J., Yau, V., Yang, Y. Gigaxonin-controlled degradation of MAP1B light chain is critical to neuronal survival. Nature 438: 224-228, 2005. [PubMed: 16227972] [Full Text: https://doi.org/10.1038/nature04256]
Cui, L., Zheng, J., Zhao, Q., Chen, J.-R., Liu, H., Peng, G., Wu, Y., Chen, C., He, Q., Shi, H., Yin, S., Friedman, R. A., Chen, Y., Guan, M.-X. Mutations of MAP1B encoding a microtubule-associated phosphoprotein cause sensorineural hearing loss. JCI Insight 5: e136046, 2020. [PubMed: 33268592] [Full Text: https://doi.org/10.1172/jci.insight.136046]
Edelmann, W., Zervas, M., Costello, P., Roback. L., Fischer, I., Hammarback, J. A., Cowan, N., Davies, P., Wainer, B., Kucherlapati, R. Neuronal abnormalities in microtubule-associated protein 1B mutant mice. Proc. Nat. Acad. Sci. 93: 1270-1275, 1996. [PubMed: 8577753] [Full Text: https://doi.org/10.1073/pnas.93.3.1270]
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Heinzen, E. L., O'Neill, A. C., Zhu, X., Allen, A. S., Bahlo, M., Chelly, J., Chen, M. H., Dobyns, W. B., Freytag, S., Guerrini, R., Leventer, R. J., Poduri, A., Robertson, S. P., Walsh, C. A., Zhang, M., Epi4K Consortium, Epilepsy Phenome/Genome Project. De novo and inherited private variants in MAP1B in periventricular nodular heterotopia. PLoS Genet. 14: e1007281, 2018. Note: Electronic Article. [PubMed: 29738522] [Full Text: https://doi.org/10.1371/journal.pgen.1007281]
Julca, D. M., Diaz, J., Berger, S., Leon, E. MAP1B related syndrome: case presentation and review of literature. Am. J. Med. Genet. 179A: 1703-1308, 2019. [PubMed: 31317654] [Full Text: https://doi.org/10.1002/ajmg.a.61280]
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Lien, L. L., Feener, C. A., Fischbach, N., Kunkel, L. M. Cloning of human microtubule-associated protein 1B and the identification of a related gene on chromosome 15. Genomics 22: 273-280, 1994. [PubMed: 7806212] [Full Text: https://doi.org/10.1006/geno.1994.1384]
Scales, T. M. E., Lin, S., Kraus, M., Goold, R. G., Gordon-Weeks, P. R. Nonprimed and DYRK1A-primed GSK3-beta-phosphorylation sites on MAP1B regulate microtubule dynamics in growing axons. J. Cell Sci. 122: 2424-2435, 2009. [PubMed: 19549690] [Full Text: https://doi.org/10.1242/jcs.040162]
Walters, G. B., Gustafsson, O., Sveinbjornsson, G., Eiriksdottir, V. K., Agustsdottir, A. B., Jonsdottir, G. A., Steinberg, S., Gunnarsson, A. F., Magnusson, M. I., Unnsteinsdottir, U., Lee, A. L., Jonasdottir, A., and 16 others. MAP1B mutations cause intellectual disability and extensive white matter deficit. Nature Commun. 9: 3456, 2018. Note: Electronic Article. [PubMed: 30150678] [Full Text: https://doi.org/10.1038/s41467-018-05595-6]
Wirth, B., Voosen, B., Rohrig, D., Knapp, M., Piechaczek, B., Rudnik-Schoneborn, S., Zerres, K. Fine mapping and narrowing of the genetic interval of the spinal muscular atrophy region by linkage studies. Genomics 15: 113-118, 1993. [PubMed: 8432521] [Full Text: https://doi.org/10.1006/geno.1993.1018]
Zhang, Y. Q., Bailey, A. M., Matthies, H. J. G., Renden, R. B., Smith, M. A., Speese, S. D., Rubin, G. M., Broadie, K. Drosophila fragile X-related gene regulates the MAP1B homolog Futsch to control synaptic structure and function. Cell 107: 591-603, 2001. [PubMed: 11733059] [Full Text: https://doi.org/10.1016/s0092-8674(01)00589-x]