During the previous funding period we discovered the pathogenic role of two proteins in neurological disease. By positional cloning the mouse neurological mutant pale tremor, with neurodegeneration in peripheral ganglia and CNS, we demonstrated that this disorder is caused by a null mutation of FIG4, a phosphatidyl inositol 5 phosphatase. We identified mutations of human FIG4 in patients with a severe form of Charcot Marie Tooth disease, a peripheral neuropathy. We also found that mutation of the functionally related protein VAC14 mimics the phenotype of the pale tremor mouse. To further evaluate the role of this pathway in neurological disease, we will characterize mouse models of human mutations in FIG4 and dissect the pathogenic contributions of neurons and Schwann cells using conditional mutants. We will evaluate the contribution of VAC14 to Charcot Marie Tooth disease, and extend the analysis of both genes to related neurological disorders. In order to identify additional components of this regulatory pathway, we will clone the modifier locus in strain C57BL/6J that exacerbates clinical progression in FIG4 null mice and investigate the in vivo phenotypes associated with mutation of the third enzyme in this pathway, a phosphoinositide kinase. We will evaluate the interaction of FIG4 with proteins recently identified in a yeast 2 hybrid screen. This work will extend our understanding of the mechanisms of pathogenesis of mutations in FIG4 and VAC14 and better define their contribution to human neurological disease.

Public Health Relevance

During the past funding period, we discovered that a lipid signaling molecule in required for survival of neurons. We found that mutations in a novel mammalian gene change the concentration of this cellular signal and result in severe neurological disease in the mouse. We were also successful in translating this information into the clinical realm by identifying patient mutations and developing molecular diagnosis for Charcot Marie Tooth disorder type 4J. We propose to extend this work to related genes and disorders, and to generate better animal models of the human disease in order to understand the pathogenic mechanism and provide an accurate model for testing therapeutic intervention.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Genetics of Health and Disease Study Section (GHD)
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Krasnewich, Donna M
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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Stutterd, Chloe; Diakumis, Peter; Bahlo, Melanie et al. (2017) Neuropathology of childhood-onset basal ganglia degeneration caused by mutation of VAC14. Ann Clin Transl Neurol 4:859-864
Lenk, Guy M; Szymanska, Krystyna; Debska-Vielhaber, Grazyna et al. (2016) Biallelic Mutations of VAC14 in Pediatric-Onset Neurological Disease. Am J Hum Genet 99:188-94
Mironova, Yevgeniya A; Lenk, Guy M; Lin, Jing-Ping et al. (2016) PI(3,5)P2 biosynthesis regulates oligodendrocyte differentiation by intrinsic and extrinsic mechanisms. Elife 5:
Lenk, Guy M; Frei, Christen M; Miller, Ashley C et al. (2016) Rescue of neurodegeneration in the Fig4 null mouse by a catalytically inactive FIG4 transgene. Hum Mol Genet 25:340-7
Vaccari, Ilaria; Carbone, Antonietta; Previtali, Stefano Carlo et al. (2015) Loss of Fig4 in both Schwann cells and motor neurons contributes to CMT4J neuropathy. Hum Mol Genet 24:383-96
Lenk, Guy M; Meisler, Miriam H (2014) Mouse models of PI(3,5)P2 deficiency with impaired lysosome function. Methods Enzymol 534:245-60
Menezes, Manoj P; Waddell, Leigh; Lenk, Guy M et al. (2014) Whole exome sequencing identifies three recessive FIG4 mutations in an apparently dominant pedigree with Charcot-Marie-Tooth disease. Neuromuscul Disord 24:666-70
Baulac, Stéphanie; Lenk, Guy M; Dufresnois, Béatrice et al. (2014) Role of the phosphoinositide phosphatase FIG4 gene in familial epilepsy with polymicrogyria. Neurology 82:1068-75
Campeau, Philippe M; Lenk, Guy M; Lu, James T et al. (2013) Yunis-Varón syndrome is caused by mutations in FIG4, encoding a phosphoinositide phosphatase. Am J Hum Genet 92:781-91
Reifler, Aaron; Lenk, Guy M; Li, Xingli et al. (2013) Murine Fig4 is dispensable for muscle development but required for muscle function. Skelet Muscle 3:21

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