Exome Sequencing Identifies a DYNC1H1 Mutation in a Large Pedigree with Dominant Axonal Charcot-Marie-Tooth Disease

Abstract

Charcot-Marie-Tooth disease is characterized by length-dependent axonal degeneration with distal sensory loss and weakness, deep-tendon-reflex abnormalities, and skeletal deformities. It is caused by mutations in more than 40 genes. We investigated a four-generation family with 23 members affected by the axonal form (type 2), for which the common causes had been excluded by Sanger sequencing. Exome sequencing of three affected individuals separated by eight meioses identified a single shared novel heterozygous variant, c.917A>G, in DYNC1H1, which encodes the cytoplasmic dynein heavy chain 1 (here, novel refers to a variant that has not been seen in dbSNP131or the August 2010 release of the 1000 Genomes project). Testing of six additional affected family members showed cosegregation and a maximum LOD score of 3.6. The shared DYNC1H1 gene variant is a missense substitution, p.His306Arg, at a highly conserved residue within the homodimerization domain. Three mouse models with different mutations within this domain have previously been reported with age-related progressive loss of muscle bulk and locomotor ability. Cytoplasmic dynein is a large multisubunit motor protein complex and has a key role in retrograde axonal transport in neurons. Our results highlight the importance of dynein and retrograde axonal transport in neuronal function in humans.

Axon Transport and Neuropathy

“…600112, http://www.ncbi.nlm.nih.gov/omim) mutations give rise to an AD form of axonal CMT, known as CMT2O. 63,64 Accordingly, heterozygous mice with an orthologous pathogenic mutation of DYNC1H1 have a marked reduction in dynein microtubule binding affinity and abnormal retrograde axon transport which produces a CMT-like motor and sensory neuropathy. 65,66 In addition, DYN-interacting proteins that function as cofactors or modulators of DYN function are identified to cause neuropathy.…”

Targeted next-generation sequencing reveals further genetic heterogeneity in axonal Charcot–Marie–Tooth neuropathy and a mutation in HSPB1

“…Both whole-genome sequencing and whole-exome sequencing (WES) have already been successfully employed in CMT mutation discovery. [6][7][8] One of the disadvantages of these methods is that they require very large amounts of sequencing to achieve sufficient read coverage for confidential exclusion of heterozygous variants in all candidate genes. For example in WES, the sequence reads are often unevenly distributed over the exome, and thus the average read coverage reveals little about the method's power to find or exclude all possible disease-causing mutations.…”

Quand le NGS aide à résoudre une énigme diagnostique

“…Il a ainsi été prouvé la survenue d'altérations morphologiques mitochondriales et d'une perte de la mitofusine 1 en particulier, soulignant là encore la physiopathologie commune avec les CMT axonaux par mutation du gène MFN2 [8]. Chez l'homme, la publication princeps de Weedon et al [9] a prouvé en 2011 l'implication de DYNC1H1 dans une large famille multiplex comprenant 23 patients sur quatre générations atteints de CMT axonal. Le phénotype rapporté était celui d'un CMT « classique » (décalage des acquisitions motrices initiales, atteinte distale avec pieds creux, atteinte rare aux membres supérieurs, maintien d'une ambulation à l'âge adulte) avec néan-moins des éléments inhabituels chez certains sujets, tel que la persistance des réflexes ou de la proprioception, une prédominance proximale voire scapulaire du déficit moteur, ou enfin des éléments céré-belleux.…”