Title
Novel mutations in the DYNC1H1 tail domain refine the genetic and clinical spectrum of dyneinopathies Novel mutations in the DYNC1H1 tail domain refine the genetic and clinical spectrum of dyneinopathies
Author
Faculty/Department
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences . Biomedical Sciences
Publication type
article
Publication
New York, N.Y. ,
Subject
Biology
Human medicine
Source (journal)
Human mutation. - New York, N.Y.
Volume/pages
36(2015) :3 , p. 287-291
ISSN
1059-7794
ISI
000351399900002
Carrier
E
Target language
English (eng)
Full text (Publishers DOI)
Affiliation
University of Antwerp
Abstract
The heavy chain 1 of cytoplasmic dynein (DYNC1H1) is responsible for movement of the motor complex along microtubules and recruitment of dynein components. Mutations in DYNC1H1 are associated with spinal muscular atrophy (SMA), hereditary motor and sensory neuropathy (HMSN), cortical malformations, or a combination of these. Combining linkage analysis and whole-exome sequencing, we identified a novel dominant defect in the DYNC1H1 tail domain (c.1792C>T, p.Arg598Cys) causing axonal HMSN. Mutation analysis of the tail region in 355 patients identified a de novo mutation (c.791G>T, p.Arg264Leu) in an isolated SMA patient. Her phenotype was more severe than previously described, characterized by multiple congenital contractures and delayed motor milestones, without brain malformations. The mutations in DYNC1H1 increase the interaction with its adaptor BICD2. This relates to previous studies on BICD2 mutations causing a highly similar phenotype. Our findings broaden the genetic heterogeneity and refine the clinical spectrum of DYNC1H1, and have implications for molecular diagnostics of motor neuron diseases.
E-info
https://repository.uantwerpen.be/docman/iruaauth/08ab33/acd2bdda8e8.pdf
https://repository.uantwerpen.be/docman/iruaauth/2ee8e0/b619933.pdf
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