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Anthony Antonellis

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Primary Appointment: Human Genetics Department
Primary PIBS Dept.: Human Genetics
Other PIBS Depts.: Neuroscience
PubMed Name: Antonellis A
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  The major focus of our research is to identify and characterize genetic loci responsible for inherited peripheral neuropathies. The end goal of these studies is a better understanding of the function of neurons and glial cells, and the molecular pathology of related diseases.

Exploring the role of aminoacyl-tRNA synthetases in neurodegenerative disease:

Aminoacyl-tRNA synthetases (ARSs) are a ubiquitously expressed, essential class of enzymes responsible for charging tRNA molecules with their cognate amino acids. We have identified mutations in the glycyl-tRNA synthetase gene (GARS, which encodes the enzyme that ligates glycine to tRNAGly molecules) in patients with two axonal peripheral neuropathies: Charcot-Marie-Tooth disease type 2D (CMT2D) and distal spinal muscular atrophy type V (dSMA-V). These findings raised immediate interest in how mutations in a ubiquitously expressed gene could lead to the limited phenotype of peripheral neuropathy. Functional analyses of GARS mutations have shown that the majority are associated with a loss of function when modeled in the yeast ortholog (GRS1). Furthermore, wild-type GARS becomes associated with granular structures present in cultured neurons and human peripheral nerve axons, while the majority of mutated forms of GARS do not; these results also suggest a loss-of-function mechanism for GARS mutations. One possible explanation for the axon-specific phenotype of CMT2D and dSMA-V is that disease-associated mutations interfere with tRNA charging, thus affecting axonal protein synthesis. In support of this, mutations in the tyrosyl-tRNA synthetase gene (YARS) have been implicated in another variant of peripheral neuropathy, and a mutation in the alanyl-tRNA synthetase gene (Aars) has been found in a mouse model of ataxia. Combined, these data suggest that ARSs have an important role in normal neuronal function. We are testing this hypothesis by: (1) Screening all 37 human ARS genes in patients with peripheral neuropathy and no known mutation; and (2) Characterizing the role of GARS in neurons using cellular and proteomic approaches.

Identifying candidate loci for inherited demyelinating peripheral neuropathy

The SRY-box containing 10 (SOX10) transcription factor has a critical role in the development and function of neural crest derivatives, including melanocytes, enteric neurons, and Schwann cells. Not surprisingly, mutations in the SOX10 gene are associated with a number of neural-crest-related phenotypes, including demyelinating peripheral neuropathy. Underscoring the importance of SOX10 in Schwann cell function are the findings that certain genes directly regulated by SOX10 (e.g., those encoding myelin protein zero [MPZ] and connexin 32 [CX32]) are frequently mutated in patients with demyelinating peripheral neuropathy. We are interested in identifying other loci regulated by SOX10 in Schwann cells. Toward this we are: (1) Computationally identifying highly-conserved SOX10 consensus sequences in the human genome; (2) Testing the surrounding genomic segments for enhancer activity in cultured Schwann cells; and (3) Identifying nearby loci that are expressed in Schwann cells. These loci, and the associated regulatory elements, will subsequently be evaluated for a role in demyelinating peripheral neuropathy.