The PNMA1 gene encodes a proapoptotic protein inducing an antineuronal antibody (anti-Ma) present in patients with paraneoplastic neurologic disorders (Dalmau et al., 1999; Chen and D'Mello, 2010).

Some paraneoplastic syndromes affecting the nervous system are associated with antibodies that react with neuronal proteins and the causal tumor (onconeuronal antigens). Several of these antibodies are markers of specific neurologic syndromes associated with distinct types of cancer. The presence of some antibodies is so specific that disorders previously identified by brain biopsy or at autopsy can be diagnosed serologically. The expression of neuronal proteins by the tumor appears to be a crucial step that breaks the immune tolerance for otherwise normal neuronal proteins. The identity of most onconeuronal antigens was established by probing human cDNA expression libraries with serum containing antineuronal antibodies (summary by Dalmau et al., 1999).

Dalmau et al. (1999) performed serologic studies of 1,705 sera from patients with suspected paraneoplastic neurologic disorders and identified 4 patients with antibodies that reacted with 37- and 40-kD (see MA2; 603970) neuronal proteins, which they referred to as anti-Ma antibodies. Three patients had brainstem and cerebellar dysfunction, and 1 had dysphagia and motor weakness. Autopsy of 2 patients showed loss of Purkinje cells, Bergmann gliosis, and deep cerebellar white matter inflammatory infiltrates. Extensive neuronal degeneration, gliosis, and infiltrates mainly composed of CD8+ T cells were also found in the brainstem of 1 patient. In normal human and rat tissues, the anti-Ma antibodies reacted exclusively with neurons and with testicular germ cells; the reaction was mainly with subnuclear elements (including the nucleoli) and to a lesser degree the cytoplasm. Anti-Ma antibodies also reacted with cancers (breast, colon, and parotid) available from 3 anti-Ma patients, but not with 66 other tumors of varying histologic types. Preincubation of tissues with any of the anti-Ma sera abrogated the reactivity of the other anti-Ma immunoglobulins. Probing of a human cDNA library with anti-Ma serum resulted in the cloning of a gene that encodes a novel 37-kD, 330-amino acid protein, which Dalmau et al. (1999) called MA1. Recombinant MA1 was specifically recognized by the 4 anti-Ma sera but not by 337 control sera, including those from 52 normal individuals, 179 cancer patients without paraneoplastic neurologic symptoms, 96 patients with paraneoplastic syndromes, and 10 patients with non-cancer-related neurologic disorders. Northern blot analysis showed that expression of MA1 mRNA was highly restricted to the brain and testis as an approximately 2.7-kb transcript. Subsequent analysis suggested that MA1 is likely to be a phosphoprotein.

Schuller et al. (2005) corrected the DNA and protein sequences of PNMA1. The corrected protein contains 353 amino acids rather than 330 amino acids, as reported by Dalmau et al. (1999).

By RT-PCR analysis, Chen and D'Mello (2010) found that Pnma1 expression in rats peaked in the perinatal period, when developmentally regulated neuronal death occurs. In day-7 postnatal rat brain, Pnma1 expression was highest in striatum, followed by midbrain, hippocampus, and cerebellum, with little expression in cortex and olfactory bulb. There was little to no expression in mature rat brain. Immunofluorescence microscopy demonstrated cytoplasmic expression of Pnma1 in cultured rat cerebellar granule neurons (CGNs).

Gross (2014) mapped the PNMA1 gene to chromosome 14q24.3 based on an alignment of the PNMA1 sequence (GenBank AF037364) with the genomic sequence (GRCh37).

The brain and testis are immunologically privileged by the existence of a blood-tissue barrier. In addition to this physical barrier, the MA1-expressing cells of these organs (neurons and germ cells) lack expression of the MHC class I and II antigens needed for the presentation of surface or intracellular proteins to the immune system. These findings indicated that the expression by a tumor of proteins normally restricted to immunoprivileged tissues (brain or testis) is a crucial step in the development of an immune response that may result in neurologic disease. In keeping with this model, a group of 'cancer/testis' antigens, such as melanoma-associated antigen-1 (MAGE1; 300016) and melanoma-associated antigen-3 (MAGE3; 300174), were originally identified because of their ability to elicit immune responses, usually T cell-mediated. Dalmau et al. (1999) questioned whether patients with anti-Ma antibodies also develop immunopathologic abnormalities in the testis. The only male patient in their study was lost to follow-up.

Using RT-PCR and Western blot analysis, Chen and D'Mello (2010) found that Pnma1 expression increased in cultured rat CGNs induced to die by low potassium and in cultured rat cortical neurons treated with homocysteic acid (HCA). Pnma2 (603970), Pnma3 (300675), and Moap1 (609485) showed no change in rat CGNs following low potassium treatment, whereas Pnma5 (300916) expression was also elevated in CGNs under these conditions. However, Pnma5 showed no change in cortical neurons following HCA treatment. Treatment of CGNs with short hairpin RNA against Pnma1 inhibited low potassium-induced cell death, as did overexpression of Bcl2 (151430). Induction of cell death required the N-terminal BH3-like domain of Pnma1. Chen and D'Mello (2010) concluded that PNMA1 functions to promote neuronal death.

Chen and D'Mello (2010) detected increased expression of Pnma1 in striatum of R6/2 transgenic mice, a model of Huntington disease (HD; 143100), compared with wildtype mice. They also detected increased Pnma1 expression in striatum of wildtype mice administered a succinate dehydrogenase (see 600857) inhibitor, which produces HD-like pathology, including striatal neurodegeneration and movement deficits. Chen and D'Mello (2010) proposed that elevated PNMA1 expression may contribute to neurodegenerative disorders.