Mutation analysis of genes within the dynactin complex in a cohort of hereditary peripheral neuropathies

• Published in: Clinical genetics 2016-08, Vol.90 (2), p.127-133
• Main Authors: Tey, S., Ahmad-Annuar, A., Drew, A.P., Shahrizaila, N., Nicholson, G.A., Kennerson, M.L.
• Format: Article
• Language: English
• Subjects: Activin Receptors, Type I - genetics; Charcot-Marie-Tooth; Cohort Studies; DNA Mutational Analysis; dynactin; Dynactin Complex - genetics; Exome; Gene Expression; Genes; Genetic disorders; hereditary motor neuropathies; hereditary sensory neuropathies; High-Throughput Nucleotide Sequencing; Humans; Mutation; Neurological disorders; Nucleic Acid Denaturation; Pedigree; Peripheral Nervous System Diseases - genetics; Peripheral Nervous System Diseases - pathology; peripheral neuropathies; Protein Isoforms - genetics; Protein Subunits - genetics; Proteins
• ISSN: 0009-9163; 1399-0004
• DOI: 10.1111/cge.12712

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.