Congenital Cataracts and Gut Dysmotility in a DYNC1H1 Dyneinopathy Patient

Gelineau‐Morel, Rose; Lukacs, Marshall; Weaver, K. Nicole; Hufnagel, Robert B.; Gilbert, Donald L.; Stottmann, Rolf W.

doi:10.3390/genes7100085

Cited by 24 publications

(20 citation statements)

References 24 publications

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“…NDE1 mutations also give rise to rare cases of PMG, it remains unclear how this arises, but RGC perturbations are also likely to affect basal endfeet attachment at the BM. De novo missense mutations in DYNC1H1 have also recently been associated with PMG [39,266]. Thus although this MCD is less well-known in terms of mechanisms, some common themes are emerging.…”

Section: 25bmentioning

confidence: 99%

Genetics and mechanisms leading to human cortical malformations

Romero

Bahi‐Buisson

Francis

2018

Seminars in Cell & Developmental Biology

100

109

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Section: 25bmentioning

confidence: 99%

Genetics and mechanisms leading to human cortical malformations

Romero

Bahi‐Buisson

Francis

2018

Seminars in Cell & Developmental Biology

100

109

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“…Its function is essential for numerous cellular activities, such as cell division, cell migration and the transport of subcellular cargoes. Not surprisingly, dysfunction of dynein and its cofactors contribute to a growing number of human diseases, collectively termed “dyneinopathies” [7–9], including spinal muscular atrophy (SMA) [10,11], SMA with lower extremity predominance (SMALED) [12–14], Charcot-Marie-Tooth disease (type 2) (CMT) [15], congenital cataracts and gut dysmotility [9], malformations of cortical development[16–20], and other debilitating neurodevelopmental and neurodegenerative diseases [15,18,19,21–24]. The molecular mechanisms of dynein and its cofactors, however, remain largely unknown [3,25–28], posing a major barrier to treatment of dyneinopathies.…”

Section: Introductionmentioning

confidence: 99%

Combining Structure–Function and Single-Molecule Studies on Cytoplasmic Dynein

Rao

Hülsemann

Gennerich

2017

Single Molecule Analysis

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Cytoplasmic dynein is the largest and most intricate cytoskeletal motor protein. It is responsible for a vast array of biological functions, ranging from the transport of organelles and mRNAs to the movement of nuclei during neuronal migration and the formation and positioning of the mitotic spindle during cell division. Despite its megadalton size and its complex design, recent success with the recombinant expression of the dynein heavy chain has advanced our understanding of dynein’s molecular mechanism through the combination of structure-function and single-molecule studies. Single-molecule fluorescence assays have provided detailed insights into how dynein advances along its microtubule track in the absence of load, while optical tweezers have yielded insights into the force generation and stalling behavior of dynein. Here, using the S. cerevisiae expression system, we provide improved protocols for the generation of dynein mutants and for the expression and purification of the mutated and/or tagged proteins. To facilitate single-molecule fluorescence and optical trapping assays, we further describe updated, easy-to-use protocols for attaching microtubules to coverslip surfaces. The presented protocols together with the recently solved crystal structures of the dynein motor domain will further simplify and accelerate hypothesis-driven mutagenesis and structure-function studies on dynein.

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“…Mutations in the gene encoding the heavy chain of the cytoplasmic dynein-1 (dynein) motor have repeatedly been implicated in neurological diseases (1,2,5,(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). Dynein is a 1.4 MDa complex that is responsible for the vast majority of cargo transport towards the minus ends of microtubules (17)(18)(19).…”

Section: Introductionmentioning

confidence: 99%

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

Hoang

Schlager

Carter

et al. 2016

Preprint

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Mutations in the human DYNC1H1 gene are associated with neurological diseases. DYNC1H1 encodes the heavy chain of cytoplasmic dynein-1, a 1.4 MDa motor complex that traffics organelles, vesicles and macromolecules towards microtubule minus ends. The effects of the DYNC1H1 mutations on dynein motility, and consequently their links to neuropathology, are not understood. Here, we address this issue using a recombinant expression system for human dynein coupled to single-molecule resolution in vitro motility assays. We functionally characterise 14 DYNC1H1 mutations identified in humans diagnosed with malformations in cortical development (MCD) or spinal muscular atrophy with lower extremity predominance (SMALED), as well as three mutations that cause motor and sensory defects in mice. Two of the human mutations, R1962C and H3822P, strongly interfere with dynein's core mechanochemical properties. The remaining mutations selectively compromise the processive mode of dynein movement that is activated by binding to the accessory complex dynactin and the cargo adaptor BICD2. Mutations with the strongest effects on dynein motility in vitro are associated with MCD. The vast majority of mutations do not affect binding of dynein to dynactin and BICD2, and are therefore expected to result in linkage of cargoes to dynein-dynactin complexes that have defective long-range motility. This observation offers an explanation for the dominant effects of DYNC1H1 mutations in vivo. Collectively, our results suggest that compromised processivity of cargo-motor assemblies contributes to human neurological disease and provide insight into the influence of different regions of the heavy chain on dynein motility.

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Congenital Cataracts and Gut Dysmotility in a DYNC1H1 Dyneinopathy Patient

Cited by 24 publications

References 24 publications

Genetics and mechanisms leading to human cortical malformations

Genetics and mechanisms leading to human cortical malformations

Combining Structure–Function and Single-Molecule Studies on Cytoplasmic Dynein

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

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