Alternative titles; symbols
HGNC Approved Gene Symbol: AMPH
Cytogenetic location: 7p14.1 Genomic coordinates (GRCh38): 7:38,383,704-38,631,373 (from NCBI)
Lichte et al. (1992) isolated a novel synaptic vesicle-associated protein, amphiphysin, by screening a chicken brain lambda-gt11 library with antibodies raised against chicken brain synaptic proteins. An acidic protein present also in mammalian nervous tissue, amphiphysin, was shown by immunocytochemistry to be concentrated in nerve terminals. See also amphiphysin-like (AMPHL; 601248).
David et al. (1994) found that the N- and C-terminal domains of the amphiphysin protein are highly conserved between chicken and human. Autoantibodies from patients with the stiff-man syndrome show a dominant autoepitope located in the C-terminal region, which contains an SH3 domain.
Yamamoto et al. (1995) noted that the tissue distribution of AMPH and its association with neurotransmitter vesicles make the gene a candidate for involvement in such diverse heritable disorders as those of the nervous system, certain endocrine tissues (such as the adrenal medulla, pituitary gland or endocrine pancreas), or male fertility.
Pathogenic Role of Anti-Amphiphysin Antibodies
Stiff-man syndrome (184850) is a rare disease of the central nervous system characterized by progressive rigidity of the body musculature with superimposed painful spasms. An autoimmune origin of the disease has been proposed. Approximately 60% of patients are positive for autoantibodies directed against the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD; 605363). A few patients, all women affected by breast cancer, were found to be negative for GAD autoantibodies but positive for autoantibodies directed against a 128-kD synaptic protein. De Camilli et al. (1993) found that this antigen is amphiphysin. Both GAD and amphiphysin are nonintrinsic membrane proteins that are concentrated in nerve terminals, where a pool of the 2 proteins is associated with the cytoplasmic surface of synaptic vesicles.
Wessig et al. (2003) reported a 71-year-old woman with invasive ductal carcinoma and a paraneoplastic stiff-person syndrome characterized by stiffness in the right arm, stiff and unsteady gait, and increased sweating. Anti-amphiphysin antibodies were detected in the patient's serum and CSF, and the patient temporarily responded to plasmapheresis. Postmortem studies detected antibodies in the central nervous system parenchyma, suggesting a pathogenic role.
Crystal Structure
Peter et al. (2004) solved the structure of the Drosophila amphiphysin BAR domain. It is a crescent-shaped dimer that binds preferentially to highly curved negatively charged membranes. With its amino-terminal amphipathic helix and BAR domain, amphiphysin can drive membrane curvature in vitro and in vivo. The structure is similar to that of arfaptin-2 (601638), which Peter et al. (2004) found also binds and tubulates membranes. From this, Peter et al. (2004) predicted that BAR domains are in many protein families, including sorting nexins, centaurins, and oligophrenins. The universal and minimal BAR domain is a dimerization, membrane-binding, and curvature-sensing module.
By PCR analysis of hybrid cell DNAs and by fluorescence in situ hybridization, Yamamoto et al. (1995) mapped the AMPH gene to 7p14-p13. The homologous locus Amph was mapped to the proximal region of mouse chromosome 13 by Jenkins et al. (1995).
Yamamoto et al. (1995) excluded AMPH as a candidate gene for either RP9 (180104) or dominant cystoid macular dystrophy (MDDC; 153880) by showing that AMPH maps to a different segment of the genetic map of chromosome 7, defined by microsatellite markers, than does either of the eye disorders.
Di Paolo et al. (2002) generated Amph knockout mice and found that lack of Amph caused a parallel loss of amphiphysin-2 (601248) 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.
David, C., Solimena, M., De Camilli, P. Autoimmunity in stiff-man syndrome with breast cancer is targeted to the C-terminal region of human amphiphysin, a protein similar to the yeast proteins, Rvs167 and Rvs161. FEBS Lett. 351: 73-79, 1994. [PubMed: 8076697] [Full Text: https://doi.org/10.1016/0014-5793(94)00826-4]
De Camilli, P., Thomas, A., Cofiell, R., Folli, F., Lichte, B., Piccolo, G., Meinck, H.-M., Austoni, M., Fassetta, G., Bottazzo, G., Bates, D., Cartlidge, N., Solimena, M., Kilimann, M. W. The synaptic vesicle-associated protein amphiphysin is the 128-kD autoantigen of stiff-man syndrome with breast cancer. J. Exp. Med. 178: 2219-2223, 1993. [PubMed: 8245793] [Full Text: https://doi.org/10.1084/jem.178.6.2219]
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]
Jenkins, N. A., Gilbert, D. J., Yamamoto, R., Kilimann, M. W., Copeland, N. G. Amphiphysin (Amph) maps to the proximal region of mouse chromosome 13. Genomics 28: 363-365, 1995. [PubMed: 8530056] [Full Text: https://doi.org/10.1006/geno.1995.1161]
Lichte, B., Veh, R. W., Meyer, H. E., Kilimann, M. W. Amphiphysin, a novel protein associated with synaptic vesicles. EMBO J. 11: 2521-2530, 1992. Note: Erratum: EMBO J. 11 3809 only, 1992. [PubMed: 1628617] [Full Text: https://doi.org/10.1002/j.1460-2075.1992.tb05317.x]
Peter, B. J., Kent, H. M., Mills, I. G., Vallis, Y., Butler, P. J. G., Evans, P. R., McMahon, H. T. BAR domains as sensors of membrane curvature: the amphiphysin BAR structure. Science 303: 495-499, 2004. [PubMed: 14645856] [Full Text: https://doi.org/10.1126/science.1092586]
Wessig, C., Klein, R., Schneider, M. F., Toyka, K. V., Naumann, M., Sommer, C. Neuropathology and binding studies in anti-amphiphysin-associated stiff-person syndrome. Neurology 61: 195-198, 2003. [PubMed: 12874398] [Full Text: https://doi.org/10.1212/01.wnl.0000073143.53337.dd]
Yamamoto, R., Li, X., Francke, U., Kilimann, M. W. Genetic mapping of the human amphiphysin gene (AMPH) at 7p14-p13 excludes its involvement in retinitis pigmentosa 9 or dominant cystoid macular dystrophy. (Letter) Am. J. Hum. Genet. 57: 970-972, 1995. [PubMed: 7573063]
Yamamoto, R., Li, X., Winter, S., Francke, U., Kilimann, M. W. Primary structure of human amphiphysin, the dominant autoantigen of paraneoplastic Stiff-Man syndrome, and mapping of its gene (AMPH) to chromosome 7p13-p14. Hum. Molec. Genet. 4: 265-268, 1995. [PubMed: 7757077] [Full Text: https://doi.org/10.1093/hmg/4.2.265]