Mutation screen reveals novel variants and expands the phenotypes associated with DYNC1H1

Abstract

Dynein, cytoplasmic 1, heavy chain 1 (DYNC1H1) encodes a necessary subunit of the cytoplasmic dynein complex, which traffics cargo along microtubules. Dominant DYNC1H1 mutations are implicated in neural diseases, including spinal muscular atrophy with lower extremity dominance (SMA-LED), intellectual disability with neuronal migration defects, malformations of cortical development (MCD), and Charcot-Marie-Tooth disease, type 2O (CMT2O). We hypothesized that additional variants could be found in these and novel motoneuron and related diseases. Therefore we analysed our database of 1,024 whole exome sequencing samples of motoneuron and related diseases for novel single nucleotide variations. We filtered these results for significant variants, which were further screened using segregation analysis in available family members. Analysis revealed six novel, rare, and highly conserved variants. Three of these are likely pathogenic and encompass a broad phenotypic spectrum with distinct disease clusters. Our findings suggest that DYNC1H1 variants can cause not only lower, but also upper motor neuron disease. It thus adds DYNC1H1 to the growing list of spastic paraplegia related genes in microtubule-dependent motor protein pathways.

FIG4 variants in central European patients with amyotrophic lateral sclerosis: a whole-exome and targeted sequencing study

“…19 Our data provide evidence for a possible link between the motor neuron disease ALS and the hereditary motor and sensory neuropathy CMT4J at the genetic and phenotypic level, comparable to the detection of deleterious variants in the DYNC1H1 (dynein, cytoplasmic 1, heavy chain 1) gene previously associated with classical CMT, in patients with UMN syndromes. 24 Deleterious biallelic variants of FIG4 were initially identified in CMT4J, 9 which is an autosomal recessive form of CMT with severe combined axonal and demyelinating peripheral neuropathy and potentially severe muscle weakness and wasting. 16 Four of the FIG4 variants identified here in ALS patients were either previously found in a compound heterozygous state with other FIG4 variants in CMT4J patients (c.122T4C and c.759delG), 9 or as heterozygous variants in patients from CMT disease cohorts (c.1940A4G and c.2558C4T).…”

DYNC1H1 mutations associated with neurological diseases compromise processivity of dynein–dynactin–cargo adaptor complexes

“…At the time of writing, more than 30 heterozygous missense mutations in the DYNC1H1 gene have been identified in patients diagnosed with spinal muscular atrophy with lower extremity predominance (SMALED) [Online Mendelian Inheritance in Man (OMIM): 158600)] or malformations of cortical development (MCD) (OMIM: 614563) (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13). SMALED is characterized by muscle weakness in the legs, which is caused by congenital or early childhood-onset loss of spinal cord motor neurons.…”

Congenital Cataracts and Gut Dysmotility in a DYNC1H1 Dyneinopathy Patient

“…A very recent report also identified this mutation in a patient with many similar phenotypes, including congenital cataracts, microcephaly and failure to thrive [17]. Additionally, a patient with hereditary spastic paraplegia was found to develop bilateral cataracts in childhood [7]. As DYNC1H1 is expressed in the elongating fiber cells of the lens and possibly traffics vesicles along microtubules for reorganization of the fiber cell, it is possible that mutations in the motor domain disrupt the development of the lens and result in cataracts [18].…”

“…Mutations in DYNC1H1 are associated with a wide spectrum of clinical manifestations including spinal muscular atrophy (SMA) [1,3,4,5], hereditary motor and sensory neuropathies [6], hereditary spastic paraplegia [7], malformations of cortical development (MCD), epilepsy, and intellectual disability [2,8,9]. Axonal defects are likely due to DYNC1H1 ’s role as the sole motor unit responsible for retrograde transport in axons [10].…”