The metabotropic glutamate receptor 1, GRM1: evaluation as a candidate gene for inherited forms of cerebellar ataxia

Abstract

The metabotropic glutamate (mGlu) 1 receptor, coded by the GRM1 gene, is involved in synaptic activities, learning and neuroprotection. Eleven different mouse Grm1 mutations, either induced or spontaneously occurring, have been reported, including one from our group. All the mutations result in a complex phenotype with ataxia and intention tremor in mice. Moreover, autoantibodies against mGlu1 receptor have been associated with paraneoplastic cerebellar ataxia in humans. In spite of the large clinical and genetic heterogeneity displayed by the inherited forms of cerebellar ataxia, forms remain with a yet unknown molecular definition. With the evidence coming out from mouse models and from paraneoplastic ataxia, it seems that GRM1 represents a good candidate gene for early-onset ataxia forms, though no GRM1 mutations have thus far been looked for. The aim of this study was to investigate the possible involvement of GRM1 in early-onset or familial forms of ataxia. We searched for gene mutations in a panel of patients with early-onset ataxia as yet molecularly undefined. No causative mutations were found, though we detected synonymous variants in the exons and changes in flanking intronic sequences which are unlikely to alter correct splicing upon bioinformatics prediction. As for other known forms of inherited ataxias, absence of mutations in GRM1 seems to suggest a relatively low frequency in cerebellar ataxias.

Pharmacological characterization of mGlu1 receptors in cerebellar granule cells reveals biased agonism

“…Understanding the signaling of mGlu 1 receptors in physiological systems is vital as these receptors may be involved in the pathophysiology of numerous diseases (Nicoletti et al, 2011). Notably, loss of mGlu 1 receptor function may contribute to the pathology of spinocerebellar ataxias (Guergueltcheva et al, 2012; Mitsumura et al, 2011; Rossi et al, 2010), and activation of mGlu 1 receptors using a positive allosteric modulator has shown therapeutic potential in ataxic mice (Notartomaso et al, 2013). These findings highlight the importance of mGlu 1 receptors in cerebellar physiology and emphasize the need to fully understand the signal transduction mediated by mGlu 1 receptors in native systems.…”

Assessment of copy number variations in 120 patients with Poland syndrome

“…quantitative polymerase chain reaction (qPCR), was obtained for de novo and/or unreported CNVs identified in PS patients (Additional file 1) according to established protocols [16]. Briefly, DNA from the patients was analyzed together with DNA from one healthy adult used as control.…”

“…A region on chromosome 12 encompassing the GAPDH gene (NM_002046.3) was used as internal control to determine copy number and normalize primer efficiency (primer sequences are available on request). qPCR was performed using the iCycler (Biorad, Hercules, CA) with Sybr Green, and the comparative DDCt method as previously described [16, 17]. …”

A Truncated Retrotransposon Disrupts the GRM1 Coding Sequence in Coton de Tulear Dogs with Bandera's Neonatal Ataxia

“…29 Nonetheless, no GRM1 mutations have been reported so far in DNA from ataxic infants. 30 On the other hand, rare cases of adult-onset subacute cerebellar ataxia have been reported in patients with paraneoplastic or autoimmune anti-mGluR1 autoantibodies in their cerebral spinal fluid and blood plasma. 31,32 Passive transfer of some of these human anti-mGluR1 antibodies has evoked transient cerebellar ataxia in mice.…”