Alternative titles; symbols
HGNC Approved Gene Symbol: BIN1
SNOMEDCT: 240081004;
Cytogenetic location: 2q14.3 Genomic coordinates (GRCh38): 2:127,048,023-127,107,154 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q14.3 | Centronuclear myopathy 2 | 255200 | Autosomal recessive | 3 |
BIN1 (AMPH2) is a novel human gene product with features of a tumor suppressor protein (Negorev et al., 1996). It was identified in a 2-hybrid screen for proteins that interact with the MYC oncoprotein (190080). Loss of BIN1 expression appears to be a frequent aberration in human hepatocellular carcinomas.
Sakamuro et al. (1996) described the product of the BIN1 gene. The predicted 451-amino acid, 50,049-Da polypeptide contains a nuclear localization signal, an SH3 (SRC homology-3) domain, a MYC-interacting domain, and a BAR (Bin1/Amphiphysin/RVS167) domain.
Wechsler-Reya et al. (1997) identified several alternately spliced BIN1 isoforms that are expressed in a cell type-specific manner. One spliced exon encodes part of the MYC-binding domain, suggesting that splicing controls the MYC-binding capacity of BIN1. Four other alternately spliced exons encode amphiphysin-related sequences that are included in brain-specific BIN1 species.
By immunohistochemical analysis of a human tissue panel, DuHadaway et al. (2003) found that specific splice isoforms of BIN1 showed unique tissue and subcellular distributions.
Mao et al. (1999) cloned mouse Bin1. Mouse and human Bin1 share about 95% sequence identity. Immunohistochemical analysis of embryonic day-10.5 mouse embryos detected Bin1 in myotomes.
By PCR analysis of somatic cell hybrids and by fluorescence in situ hybridization, Negorev et al. (1996) mapped the BIN1 gene to chromosome 2q14.
By interspecific backcross analysis, Mao et al. (1999) mapped the mouse Bin1 gene to the proximal region of chromosome 18.
Wechsler-Reya et al. (1997) detected 19 exons of the BIN1 gene and determined that it spans more than 54 kb. The 5-prime flanking region is GC-rich and lacks a TATA box. The promoter region contains a MYOD (159970) consensus binding site.
Nicot et al. (2007) stated that the BIN1 gene comprises 20 exons and noted the presence of at least 10 different isoforms produced by alternative splicing.
Mao et al. (1999) determined that the 5-prime flanking region of the mouse promoter does not contain the Myod consensus site found in the human gene, but there are weak sites for Mef2 (600660) and Tef (188595). The mouse promoter also does not have a CpG island. Both the human and mouse promoters have a nuclear factor kappa- B (NFKB; see 164011)-binding site.
The structural relationship between BIN1, the breast cancer-associated autoimmune antigen amphiphysin (AMPH; 600418), and the yeast negative cell cycle regulator RVS167 suggested to Sakamuro et al. (1996) that BIN1 has roles in malignancy and cell cycle control. Consistent with this likelihood, Sakamuro et al. (1996) found that BIN1 inhibited malignant cell transformation by MYC. Although BIN1 is expressed in many normal cells, its levels were greatly reduced or undetectable in 14 of 27 carcinoma cell lines and 3 of 6 primary breast tumors. The authors stated that the deficits were functionally significant because ectopic expression of BIN1 inhibited the growth of tumor cells lacking endogenous BIN1 message. Sakamuro et al. (1996) concluded that BIN1 is a MYC-interacting protein with features of a tumor suppressor.
Using serum withdrawal to induce differentiation in a mouse myogenic cell line, Wechsler-Reya et al. (1998) determined that differentiation was associated with an upregulation of Bin1 mRNA and protein and with the generation of alternately spliced higher molecular mass forms of Bin1. In undifferentiated cells, Bin1 localized exclusively in the nucleus, and differentiation-associated isoforms were also found in the cytoplasm. Cells overexpressing human BIN1 grew more slowly than control myoblasts, and they differentiated more rapidly when deprived of growth factors. In contrast, myoblasts expressing antisense BIN1 showed an impaired ability to undergo differentiation. Using the same mouse myogenic cell line, Mao et al. (1999) found that antisense Bin1 prevented induction of the cell cycle kinase inhibitor p21/WAF1 (CDKN1A; 116899), suggesting that it acts at an early time during muscle differentiation.
BIN1 is concentrated at T tubules in striated muscle and induces tubular plasma membrane invaginations when expressed in nonmuscle cells. Lee et al. (2002) determined that this property requires exon 10, a phosphoinositide-binding module. In developing myotubes, BIN1 and caveolin-3 (601253) segregated in tubular and vesicular portions of the T-tubule system, respectively. Lee et al. (2002) concluded that their findings supported a role of the bilayer-deforming properties of amphiphysin at T tubules and, more generally, a physiologic role of amphiphysin in membrane deformation. In developing myocytes, Lee et al. (2002) confirmed that BIN1 expression increased upon differentiation, and they found it correlated with increased expression of caveolin and the dihydropyridine receptor (114208), a calcium channel of T tubules, and with the downregulation of caveolin-1 (601047).
Wixler et al. (1999) identified BIN1 as a binding partner of integrin alpha-3 (605025) in a yeast 2-hybrid screen of a placenta cDNA library. Using the conserved C-terminal motif of several other alpha-integrin subunits, they found that BIN1 bound specifically to integrins that are laminin receptors, including alpha-1 (192968), alpha-3A, alpha-3B, and alpha-6B (147556).
Fugier et al. (2011) demonstrated that alternative splicing of the BIN1 gene was disrupted in muscle cells derived from patients with DM1 (160900) and DM2 (602668). Exon 11 of BIN1 mRNA was skipped, and the amount of skipped mRNA correlated with disease severity. This splicing misregulation was associated with sequestration of the splicing regulator MBNL1 due to pathogenic expanded CUG or CCUG repeats. Expression of BIN1 without exon 11 resulted in little or no T-tubule formation in cultured muscle cells, since this splice variant lacks a phosphatidylinositol 5-phosphate-binding site necessary for membrane-tubulating activities. Skeletal muscle biopsies from patients with DM1 showed disorganized BIN1 localization and irregular T-tubule networks. Promotion of the skipping of Bin1 exon 11 in mouse skeletal muscle resulted in abnormal T tubules and decreased muscle strength, although muscle integrity was maintained. There was also decreased expression of Cacna1s (114208), which plays a role in the excitation-contraction coupling process. The findings suggested a link between abnormal BIN1 expression and muscle weakness in myotonic dystrophy, and confirmed the role of BIN1 in T-tubule structure.
Using yeast 2-hybrid, pull-down, and coimmunoprecipitation analyses, Nakajo et al. (2016) identified mouse Ehbp1l1 (619583) as a Rab8 (RAB8A; 165040)-binding protein. Ehbp1l1 also bound Bin1, with the proline-rich domain of Ehbp1l1 interacting with the C-terminal SH3-containing region of Bin1. By interacting, Rab8, Ehbp1l1, and Bin1 stabilized their localization at the ECR. The Rab8-Ehbp1l1-Bin1 complex played a role in transport of apical and basolateral cargo proteins through the ERC to the apical plasma membrane in polarized epithelial cells by sensing and generating membrane tubules to transport cargo, likely with the involvement of dynamin.
To better understand common genetic variation associated with brain diseases, Nott et al. (2019) defined noncoding regulatory regions for major cell types of the human brain. Whereas psychiatric disorders were primarily associated with variants in transcriptional enhancers and promoters in neurons, sporadic Alzheimer disease (see 104300) variants were largely confined to microglia enhancers. Interactome maps connecting disease-risk variants in cell type-specific enhancers to promoters revealed an extended microglia gene network in Alzheimer disease. Deletion of a microglia-specific enhancer harboring Alzheimer-risk variants ablated BIN1 expression in microglia, but not in neurons or astrocytes. Nott et al. (2019) concluded that their findings revised and expanded the list of genes likely to be influenced by noncoding variants in Alzheimer disease and suggested the probable cell types in which they function.
In affected members of 3 unrelated consanguineous families with autosomal recessive centronuclear myopathy (CNM2; 255200), Nicot et al. (2007) identified 3 different homozygous mutations in the BIN1 gene (601248.0001-601248.0003). The findings suggested that mutations in BIN1 cause myopathy by interfering with remodeling of T tubules and/or endocytic membranes and that the functional interaction between BIN1 and DNM2 (602378) is necessary for normal muscle function and positioning of nuclei. None of the patients developed tumors.
In a Moroccan man with autosomal recessive centronuclear myopathy since childhood and mild mental retardation, Claeys et al. (2010) identified a homozygous mutation in the BIN1 gene (R154Q; 601248.0004).
Among 53 patients diagnosed with centronuclear myopathy at 5 major centers in Spain, Cabrera-Serrano et al. (2018) identified 16 who were homozygous for an arg234-to-cys (R234C; 601248.0004) mutation and 2 who were compound heterozygous for R234C and an arg145-to-cys (R145C; 601248.0005) mutation. All 15 of the known Roma patients had the R234C mutation, which was found by haplotype analysis to be a founder mutation; the remaining 3 patients were of unknown ethnic origin and were lost to follow-up.
Di Paolo et al. (2002) generated Amph knockout mice and found that lack of Amph caused a parallel loss of amphiphysin-2 selectively in brain. Cell-free assembly of endocytic protein scaffolds was defective in mutant brain extracts and there were defects in synaptic vesicle recycling. These defects correlated with major learning deficits and with increased mortality due to rare irreversible seizures, suggesting that Amph has a critical role in higher brain functions.
Using a mouse knockout model, Muller et al. (2005) demonstrated that Bin1 loss elevated the Stat1 (600555)- and Nfkb-dependent expression of indoleamine 2,3-dioxygenase (INDO; 147435), driving escape of oncogenically transformed cells from T cell-dependent antitumor immunity. In a mouse breast cancer model, coadministration of small-molecule inhibitors of Indo and cytotoxic agents elicited regression of established tumors refractory to single-agent therapy. Muller et al. (2005) suggested that BIN1 loss promotes immune escape in cancer by deregulating INDO and that INDO inhibitors may improve responses to cancer chemotherapy.
Giraud et al. (2023) treated muscle-specific Bin1 knockout mice (Bin1 mck -/-) with AAV9-mediated MTM1 overexpression (AAV-MTM1-WT). Mice that were treated with systemic injection at day of life P1 had improved muscle force, motor function, and muscle fiber size and organization. MTM1-WT overexpression also rescued AKT pathway defects present in Bin1 mck -/- muscle tissue. By treating mice with an AAV9 carrying an MTM1 with defective phosphatase activity, Giraud et al. (2023) demonstrated that the phosphatase activity was necessary for muscle hypertrophy but not for T-tubule organization. Bin1 mck -/- mice treated at 8 weeks of age with intramuscular injection of AAV-MTM1-WT had partial improvement. Giraud et al. (2023) concluded that BIN1 and MTM1 work synergistically to regulate muscle physiology.
In 2 Indian sibs with autosomal recessive centronuclear myopathy (CNM2; 255200), born of consanguineous parents, Nicot et al. (2007) identified a homozygous 105G-T transversion in the BIN1 gene, resulting in a lys35-to-asn (K35N) substitution. A third affected sib was not tested. Two sibs died at ages 18 hours and 1 year, respectively; the third was alive at 12 years. Features included contractures at birth, proximal muscle weakness, and central nuclei on skeletal muscle biopsy. The K35N substitution was predicted to alter the charge of a polybasic sequence and lead to a defect in membrane curvature. Cellular functional expression studies showed that the K35N substitution abolished muscle fiber membrane tubulation.
In a 35-year-old Iraqi man with autosomal recessive centronuclear myopathy (CNM2; 255200), born of consanguineous parents, Nicot et al. (2007) identified a homozygous 451G-A transition in the BIN1 gene resulting in an asp151-to-asn (D151N) substitution. He had onset at age 8 years of a proximal muscle weakness and had central nuclei on skeletal muscle biopsy. Cellular functional expression studies showed that the D151N substitution abolished muscle fiber membrane tubulation.
In a 14-year-old Iraqi boy with autosomal recessive centronuclear myopathy (CNM2; 255200), Nicot et al. (2007) identified a homozygous 1723A-T transversion in the BIN1 gene, resulting in a lys575-to-ter (K575X) substitution. The mutation was predicted to remove the last alpha-helix and 2 beta-strands of the SH3 domain. Cellular functional expression studies showed that the K575X mutation was unable to efficiently recruit DNM2 (602378) to membrane tubules.
In a 21-year-old Moroccan man with autosomal recessive centronuclear myopathy (CNM2; 255200) beginning in childhood, Claeys et al. (2010) identified a homozygous 461G-A transition in exon 6 of the BIN1 gene, resulting in an arg154-to-gln (R154Q) substitution in a conserved residue in the BAR domain. The mutation was not present in 280 normal controls. The patient had diffuse muscle weakness and atrophy and mild mental retardation.
In 18 patients diagnosed with centronuclear myopathy (CNM2; 255200), Cabrera-Serrano et al. (2018) identified biallelic mutations in the BIN1 gene: 16 were homozygous for a c.700C-T transition in the BIN1 gene, resulting in an arg234-to-cys (R234C) mutation, and 2 were compound heterozygous for R234C and a c.433C-T transition, resulting in an arg145-to-cys (R145C; 601248.0006) substitution. Both mutations occurred at highly conserved residues within the BAR domain and had a low carrier frequency in the gnomAD database (0.0008% for R234C and 0.0004% for R145C). All 15 of the known Spanish Roma patients had the R234C mutation, which was found by haplotype analysis to be a founder mutation; the remaining 3 patients were of unknown ethnic origin and were lost to follow-up. Screening of 758 European Roma controls for the R234C variant identified a carrier frequency of 3.5% among the Spanish Roma.
For discussion of the c.433C-T transition (c.433C-T, NM_139343) in the BIN1 gene, resulting in an arg145-to-cys (R145C) substitution, that was found in compound heterozygous state in Spanish Roma patients with centronuclear myopathy (CNM2; 255200) by Cabrera-Serrano et al. (2018), see 601248.0005.
Cabrera-Serrano, M., Mavillard, F., Biancalana, V., Rivas, E., Morar, B., Hernandez-Lain, A., Olive, M., Muelas, N., Khan, E., Carvajal, A., Quiroga, P., Diaz-Manera, J., and 10 others. A Roma founder BIN1 mutation causes a novel phenotype of centronuclear myopathy with rigid spine. Neurology 91: e339-e348, 2018. [PubMed: 29950440] [Full Text: https://doi.org/10.1212/WNL.0000000000005862]
Claeys, K. G., Maisonobe, T., Bohm, J., Laporte, J., Hezode, M., Romero, N. B., Brochier, G., Bitoun, M., Carlier, R. Y., Stojkovic, T. Phenotype of a patient with recessive centronuclear myopathy and a novel BIN1 mutation. Neurology 74: 519-521, 2010. [PubMed: 20142620] [Full Text: https://doi.org/10.1212/WNL.0b013e3181cef7f9]
Di Paolo, G., Sankaranarayanan, S., Wenk, M. R., Daniell, L., Perucco, E., Caldarone, B. J., Flavell, R., Picciotto, M. R., Ryan, T. A., Cremona, O., De Camilli, P. Decreased synaptic vesicle recycling efficiency and cognitive deficits in amphiphysin 1 knockout mice. Neuron 33: 789-804, 2002. [PubMed: 11879655] [Full Text: https://doi.org/10.1016/s0896-6273(02)00601-3]
DuHadaway, J. B., Lynch, F. J., Brisbay, S., Bueso-Ramos, C., Troncoso, P., McDonnell, T., Prendergast, G. C. Immunohistochemical analysis of Bin1/amphiphysin II in human tissues: diverse sites of nuclear expression and losses in prostate cancer. J. Cell. Biochem. 88: 635-642, 2003. [PubMed: 12532338] [Full Text: https://doi.org/10.1002/jcb.10380]
Fugier, C., Klein, A. F., Hammer, C., Vassilopoulos, S., Ivarsson, Y., Toussaint, A., Tosch, V., Vignaud, A., Ferry, A., Messaddeq, N., Kokunai, Y., Tsuburaya, R., and 22 others. Misregulated alternative splicing of BIN1 is associated with T tubule alterations and muscle weakness in myotonic dystrophy. (Letter) Nature Med. 17: 720-725, 2011. [PubMed: 21623381] [Full Text: https://doi.org/10.1038/nm.2374]
Giraud, Q., Spiegelhalter, C., Messaddeq, N., Laporte, J. MTM1 overexpression prevents and reverts BIN1-related centronuclear myopathy. Brain 146: 4158-4173, 2023. [PubMed: 37490306] [Full Text: https://doi.org/10.1093/brain/awad251]
Lee, E., Marcucci, M., Daniell, L., Pypaert, M., Weisz, O. A., Ochoa, G.-C., Farsad, K., Wenk, M. R., De Camilli, P. Amphiphysin 2 (Bin1) and T-tubule biogenesis in muscle. Science 297: 1193-1196, 2002. [PubMed: 12183633] [Full Text: https://doi.org/10.1126/science.1071362]
Mao, N.-C., Steingrimsson, E., DuHadaway, J., Wasserman, W., Ruiz, J. C., Copeland, N. G., Jenkins, N. A., Prendergast, G. C. The murine Bin1 gene functions early in myogenesis and defines a new region of synteny between mouse chromosome 18 and human chromosome 2. Genomics 56: 51-58, 1999. [PubMed: 10036185] [Full Text: https://doi.org/10.1006/geno.1998.5709]
Muller, A. J., DuHadaway, J. B., Donover, P. S., Sutanto-Ward, E., Prendergast, G. C. Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy. Nature Med. 11: 312-319, 2005. [PubMed: 15711557] [Full Text: https://doi.org/10.1038/nm1196]
Nakajo, A., Yoshimura, S., Togawa, H., Kunii, M., Iwano, T., Izumi, A., Noguchi, Y. Watanabe, A., Goto, A., Sato, T., Harada, A. EHBP1L1 coordinates Rab8 and Bin1 to regulate apical-directed transport in polarized epithelial cells. J. Cell Biol. 212: 297-306, 2016. [PubMed: 26833786] [Full Text: https://doi.org/10.1083/jcb.201508086]
Negorev, D., Riethman, H., Wechsler-Reya, R., Sakamuro, D., Prendergast, G. C., Simon, D. The Bin1 gene localizes to human chromosome 2q14 by PCR analysis of somatic cell hybrids and fluorescence in situ hybridization. Genomics 33: 329-331, 1996. [PubMed: 8725406] [Full Text: https://doi.org/10.1006/geno.1996.0205]
Nicot, A.-S., Toussaint, A., Tosch, V., Kretz, C., Wallgren-Petterson, C., Iwarsson, E., Kingston, H., Garnier, J.-M., Biancalana, V., Oldfors, A., Mandel, J.-L., Laporte, J. Mutations in amphiphysin 2 (BIN1) disrupt interaction with dynamin 2 and cause autosomal recessive centronuclear myopathy. (Letter) Nature Genet. 39: 1134-1139, 2007. [PubMed: 17676042] [Full Text: https://doi.org/10.1038/ng2086]
Nott, A., Holtman, I. R., Coufal, N. G., Schlachetzki, J. C. M., Yu, M., Hu, R., Han, C. Z., Pena, M., Xiao, J., Wu, Y., Keulen, Z., Pasillas, M. P., and 14 others. Brain cell type-specific enhancer-promoter interactome maps and disease-risk association. Science 366: 1134-1139, 2019. [PubMed: 31727856] [Full Text: https://doi.org/10.1126/science.aay0793]
Sakamuro, D., Elliott, K. J., Wechsler-Reya, R., Prendergast, G. C. BIN1 is a novel MYC-interacting protein with features of a tumour suppressor. Nature Genet. 14: 69-77, 1996. [PubMed: 8782822] [Full Text: https://doi.org/10.1038/ng0996-69]
Wechsler-Reya, R. J., Elliott, K. J., Prendergast, G. C. A role for the putative tumor suppressor Bin1 in muscle cell differentiation. Molec. Cell. Biol. 18: 566-575, 1998. [PubMed: 9418903] [Full Text: https://doi.org/10.1128/MCB.18.1.566]
Wechsler-Reya, R., Sakamuro, D., Zhang, J., Duhadaway, J., Prendergast, G. C. Structural analysis of the human BIN1 gene: evidence for tissue-specific transcriptional regulation and alternate RNA splicing. J. Biol. Chem. 272: 31453-31458, 1997. [PubMed: 9395479] [Full Text: https://doi.org/10.1074/jbc.272.50.31453]
Wixler, V., Laplantine, E., Geerts, D., Sonnenberg, A., Petersohn, D., Eckes, B., Paulsson, M., Aumailley, M. Identification of novel interaction partners for the conserved membrane proximal region of alpha-integrin cytoplasmic domains. FEBS Lett. 445: 351-355, 1999. [PubMed: 10094488] [Full Text: https://doi.org/10.1016/s0014-5793(99)00151-9]