Poster Presentation 9th GeneMappers Conference 2012

Analysis of Dynein-Dynactin Genes in Inherited Peripheral Neuropathies (#101)

Shelisa Tey 1 , Azlina Ahmad Annuar 1 , Nortina Shahrizaila 2 , Alexender P Drew 3 , Garth A Nicholson 3 , Marina L Kennerson 3
  1. Department of Molecular Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
  2. Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
  3. Northcott Neuroscience Laboratory, ANZAC Research Institute, Concord, NSW, Australia

Inherited peripheral neuropathies can be divided into subgroups based on the involvement of motor and or sensory neurons.  They are a clinically and genetically heterogeneous group of disorders with over 60 loci reported and more than 44 genes identified. Charcot Marie Tooth’s disease (CMT) is the most common inherited peripheral neuropathy with a prevalence of 1/2500 and involved both motor and sensory loss. Hereditary Sensory Neuropathies (HSN) is less common than CMT and primarily involves the sensory neurons. The dynein-dynactin complex is composed of numerous subunits including the heavy chain, intermediate chains, light intermediate chains, light chains and dynactin subunits. Several mouse models with Dync1h1 mutations suggest the involvement of cytoplasmic dynein in motor and sensory neuropathies, also mutations in dynein heavy chain 1 (DYNC1H1) are reported to cause CMT. We hypothesis that mutations in genes encoding subunits of this complex will disrupt retrograde transport and lead to axonal degeneration which is seen in CMT and HSN. The aim of our study is to screen CMT and HSN families for novel mutations in other genes of dynein-dynactin complex. The cohort includes 114 CMT and 38 HSN families in which the causative gene is unknown.  Exome sequencing and high resolution melt (HRM) screening are the approaches we have used to identify and validate novel mutations. Currently, several novel variants have been identified for DYNC1H1, DYNC1LI1 and DCTN1. Validation and segregation analysis of these variants will be presented.  No novel variants have been identified in the cytoplasmic dynein light chain for HSN samples. This study may further implicate the role of dynein-dynactin complex in the mechanism underlying axonal degeneration and provide additional therapeutic targets for the developments of disease treatment.

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