Mutation of FIG4 causes a rapidly progressive, asymmetric neuronal degeneration

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Mutation of FIG4 causes a rapidly progressive, asymmetric neuronal

degeneration

http://brain.oxfordjournals.org/cgi/content/abstract/131/8/1990?

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Xuebao Zhang1, Clement Y. Chow2, Zarife Sahenk3,4, E. Shy1,

Miriam H. Meisler2 and Jun Li1,5

1Department of Neurology, Wayne State University, School of Medicine,

Detroit, MI, 2Department of Human Genetics, University of Michigan,

Ann Arbor, MI, 3Columbus Children's Research Institute, 4Department

of Neurology, Ohio State University, Columbus, OH and 5 D.

Dingell VA Medical Center, Detroit, MI, USA

Recessive Charcot-Marie-Tooth disease type-4J (CMT4J) and its animal

model, the pale tremor mouse (plt), are caused by mutations of the

FIG4 gene encoding a PI(3,5)P2 5-phosphatase. We describe the 9-year

clinical course of CMT4J, including asymmetric, rapidly progressive

paralysis, in two siblings. Sensory symptoms were absent despite

reduced numbers of sensory axons. Thus, the phenotypic presentation

of CMT4J clinically resembles motor neuron disease. Time-lapse

imaging of fibroblasts from CMT4J patients demonstrates impaired

trafficking of intracellular organelles because of obstruction by

vacuoles. Further characterization of plt mice identified axonal

degeneration in motor and sensory neurons, limited segmental

demyelination, lack of TUNEL staining and lack of accumulation of

ubiquitinated protein in vacuoles of motor and sensory neurons.

This study represents the first documentation of the natural history

of CMT4J. Physical obstruction of organelle trafficking by vacuoles

is a potential novel cellular mechanism of neurodegeneration.