The overarching objectives of this K99/ROO application are to transition to an independent investigator position, and to identify and characterize genetic loci with a role in inherited peripheral neuropathies. My long-term career goal is to establish myself as an independent investigator in the field of neurogenetics. Peripheral neuropathies are a group of diseases characterized by impaired motor function and sensory loss in the extremities. About 2.4% of the general population is affected with a peripheral neuropathy, making these diseases a significant public health concern. A more complete understanding of the genes implicated in peripheral neuropathies will provide insight into the etiology of these diseases and aid the development of more efficient therapies. Two genes encoding enzymes that charge tRNA molecules with their cognate amino acids (ARSs) have been implicated in inherited peripheral neuropathies. My current research involves determining the molecular pathology associated with mutations in one of these genes (GARS). This work has revealed that the majority of mutations are associated with a loss of function. Furthermore, wild-type GARS becomes associated with granules in human peripheral nerve axons. I thus hypothesize that GARSassociated granules are required in axons for local tRNA charging, and that other ARSs likely play a role in inherited peripheral neuropathies. To address this I will: (Specific Aim 1) establish the protein-content and function of GARS-associated granules in axons;and (Specific Aim 2) screen all human ARS genes for mutations in DMA samples isolated from patients with inherited peripheral neuropathy. Another area of my current research involves studying the transcriptional regulation of the SOX10 locus, which encodes a transcription factor with an important role in peripheral nerve development and function. Importantly, SOX10 transcriptionally regulates certain genes that are commonly mutated in patients with peripheral neuropathy. I thus hypothesize that SOX10 transcriptionally regulates other genes important for peripheral nerve health. To address this I will (Specific Aim 3) identify and characterize SOX10-target genes in the peripheral nervous system. Completing these Specific Aims will provide: (i) a better understanding of the role of GARS in peripheral nerve axons;(ii) knowledge about the role of all ARS genes in inherited peripheral neuropathies; and (iii) a more complete panel of genes transcriptionally regulated by SOX10 in peripheral nerves. The training (K99) portion of this award will be mentored by Dr. Eric D. Green at the National Human Genome Research Institute. Dr. Green is a recognized leader in the fields of human genetics and comparative genomics.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Transition Award (R00)
Project #
5R00NS060983-04
Application #
7918813
Study Section
Special Emphasis Panel (NSS)
Program Officer
Gwinn, Katrina
Project Start
2008-09-16
Project End
2011-08-31
Budget Start
2010-09-01
Budget End
2011-08-31
Support Year
4
Fiscal Year
2010
Total Cost
$249,000
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Genetics
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Gonzalez, Michael; McLaughlin, Heather; Houlden, Henry et al. (2013) Exome sequencing identifies a significant variant in methionyl-tRNA synthetase (MARS) in a family with late-onset CMT2. J Neurol Neurosurg Psychiatry 84:1247-9
Vester, Aimée; Velez-Ruiz, Gisselle; McLaughlin, Heather M et al. (2013) A loss-of-function variant in the human histidyl-tRNA synthetase (HARS) gene is neurotoxic in vivo. Hum Mutat 34:191-9
McLaughlin, Heather M; Sakaguchi, Reiko; Giblin, William et al. (2012) A recurrent loss-of-function alanyl-tRNA synthetase (AARS) mutation in patients with Charcot-Marie-Tooth disease type 2N (CMT2N). Hum Mutat 33:244-53
Stum, Morgane; McLaughlin, Heather M; Kleinbrink, Erica L et al. (2011) An assessment of mechanisms underlying peripheral axonal degeneration caused by aminoacyl-tRNA synthetase mutations. Mol Cell Neurosci 46:432-43
Nguyen, Di Kim; Yang, Fan; Kaul, Rajinder et al. (2011) Clcn4-2 genomic structure differs between the X locus in Mus spretus and the autosomal locus in Mus musculus: AT motif enrichment on the X. Genome Res 21:402-9
Motley, William W; Seburn, Kevin L; Nawaz, Mir Hussain et al. (2011) Charcot-Marie-Tooth-linked mutant GARS is toxic to peripheral neurons independent of wild-type GARS levels. PLoS Genet 7:e1002399
Antonellis, Anthony; Dennis, Megan Y; Burzynski, Grzegorz et al. (2010) A rare myelin protein zero (MPZ) variant alters enhancer activity in vitro and in vivo. PLoS One 5:e14346
McLaughlin, Heather M; Sakaguchi, Reiko; Liu, Cuiping et al. (2010) Compound heterozygosity for loss-of-function lysyl-tRNA synthetase mutations in a patient with peripheral neuropathy. Am J Hum Genet 87:560-6
Stine, Zachary E; Huynh, Jimmy L; Loftus, Stacie K et al. (2009) Oligodendroglial and pan-neural crest expression of Cre recombinase directed by Sox10 enhancer. Genesis 47:765-70
Loftus, Stacie K; Antonellis, Anthony; Matera, Ivana et al. (2009) Gpnmb is a melanoblast-expressed, MITF-dependent gene. Pigment Cell Melanoma Res 22:99-110

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