Autoantibodies to a 128-kd Synaptic Protein in Three Women with the Stiff-Man Syndrome and Breast Cancer

Abstract

In a subgroup of patients with the stiff-man syndrome, the condition is likely to have an autoimmune paraneoplastic origin. The detection of autoantibodies against the 128-kd antigen in patients with this syndrome should be considered an indication to search for an occult breast cancer.

A role of amphiphysin in synaptic vesicle endocytosis suggested by its binding to dynamin in nerve terminals.

“…In this study we have explored the possibility that amphiphysin, a neuronal SH3 domain-containing protein selectively concentrated in axon endings (15-17), may represent a physiological partner for dynamin. Amphiphysin is a hydrophilic, highly acidic protein, which is found in soluble and particulate fractions of brain homogenates including synaptic vesicle membranes but is not enriched in purified synaptic vesicles (15)(16)(17) MATERIALS AND METHODS Antibodies. Polyclonal antibodies (CD5 and CD6) directed against full-length glutathione S-transferase (GST)-amphiphysin were raised in rabbits and affinity purified on polyhistidinetagged amphiphysin (His-amph) fusion proteins.…”

“…However, none of these proteins was shown to be concentrated in nerve terminals and the significance of these interactions for synaptic vesicle recycling remains unclear. In this study we have explored the possibility that amphiphysin, a neuronal SH3 domain-containing protein selectively concentrated in axon endings (15)(16)(17), may represent a physiological partner for dynamin. Amphiphysin is a hydrophilic, highly acidic protein, which is found in soluble and particulate fractions of brain homogenates including synaptic vesicle membranes but is not enriched in purified synaptic vesicles (15)(16)(17).…”

Antibodies against cell adhesion molecules and neural structures in paraneoplastic neuropathies

“…Since the description of anti‐Hu antibodies in 1985,35 and following the identification of other highly specific onconeural antibodies in the serum of PNS patients,37, 38, 39, 40, 41, 42, 43 current hypotheses suggest an autoimmune origin in PNS 1. According to the location of the antigen, two types of antibodies have been described in these conditions: antibodies targeting cell membrane antigens or antibodies against intracellular antigens, being the latter defined as onconeural 44.…”

Stiff-man syndrome: From the bedside to the bench

“…These patients have circulating non-organ-specific autoantibodies, but are anti-GAD and anti-islet cell antibody negative. Folli et al (51) described the presence of an antibody to a 128-kd protein in 2 SMS patients with breast cancer and 1 patient with previously undetected invasive ductal carcinoma of the breast. The antigen was subsequently identified as amphiphysin, a nonintrinsic membrane protein concentrated in nerve terminals, where a pool of both GAD and amphiphysin was associated with the cytoplasmic surface of synaptic vesicles (52).…”

“…At first glance, the expression of GAD and amphiphysin on the cytoplasmic surface of plasma membranes would preclude their interaction with autoantibodies. Ellis and Atkinson (54) have proposed that the autoantibodies could potentiate a functional impairment of GABAergic transmission by blocking membrane-associated GAD during the exocytosis of GABA (51). The presence of antiamphiphysin antibody should prompt a thorough search for an underlying malignancy.…”