title: Mutation analysis of genes within the dynactin complex in a cohort of hereditary peripheral neuropathies.
abstract: The cytoplasmic dynein-dynactin genes are attractive candidates for neurodegenerative disorders given their functional role in retrograde transport along neurons. The cytoplasmic dynein heavy chain (DYNC1H1) gene has been implicated in various neurodegenerative disorders, and dynactin 1 (DCTN1) genes have been implicated in a wide spectrum of disorders including motor neuron disease, Parkinson's disease, spinobulbar muscular atrophy and hereditary spastic paraplegia. However, the involvement of other dynactin genes with inherited peripheral neuropathies (IPN) namely, hereditary sensory neuropathy, hereditary motor neuropathy and Charcot-Marie-Tooth disease is under reported. We screened eight genes; DCTN1-6 and ACTR1A and ACTR1B in 136 IPN patients using whole-exome sequencing and high-resolution melt (HRM) analysis. Eight non-synonymous variants (including one novel variant) and three synonymous variants were identified. Four variants have been reported previously in other studies, however segregation analysis within family members excluded them from causing IPN in these families. No variants of disease significance were identified in this study suggesting the dynactin genes are unlikely to be a common cause of IPNs. However, with the ease of querying gene variants from exome data, these genes remain worthwhile candidates to assess unsolved IPN families for variants that may affect the function of the proteins.
authors.affiliation: Department of Biomedical Science, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: S
authors.initials: S
authors.lastname: Tey
authors.affiliation: Department of Biomedical Science, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: A
authors.initials: A
authors.lastname: Ahmad-Annuar
authors.affiliation: Northcott Neuroscience Laboratory, ANZAC Research Institute, and Sydney Medical School, University of Sydney, Sydney, Australia.
authors.forename: A P
authors.initials: AP
authors.lastname: Drew
authors.affiliation: Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: N
authors.initials: N
authors.lastname: Shahrizaila
authors.affiliation: Northcott Neuroscience Laboratory, ANZAC Research Institute, and Sydney Medical School, University of Sydney, Sydney, Australia.|Molecular Medicine Laboratory, Concord Hospital, Sydney, Australia.
authors.forename: G A
authors.initials: GA
authors.lastname: Nicholson
authors.affiliation: Northcott Neuroscience Laboratory, ANZAC Research Institute, and Sydney Medical School, University of Sydney, Sydney, Australia.|Molecular Medicine Laboratory, Concord Hospital, Sydney, Australia.
authors.forename: M L
authors.initials: ML
authors.lastname: Kennerson
mesh_terms: D030201:Activin Receptors, Type I / Q000235:genetics*; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D000072159:Dynactin Complex / Q000235:genetics*; D059472:Exome; D015870:Gene Expression; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009154:Mutation; D009691:Nucleic Acid Denaturation; D010375:Pedigree; D010523:Peripheral Nervous System Diseases / Q000235:genetics* / Q000473:pathology; D020033:Protein Isoforms / Q000235:genetics; D021122:Protein Subunits / Q000235:genetics*
chemical_list: C000606360:DCTN1 protein, human; D000072159:Dynactin Complex; D020033:Protein Isoforms; D021122:Protein Subunits; C425423:ACVR1 protein, human; C498932:ACVR1B protein, human; D030201:Activin Receptors, Type I
keywords: Charcot-Marie-Tooth; dynactin; hereditary motor neuropathies; hereditary sensory neuropathies; peripheral neuropathies