Beyond spinal muscular atrophy with lower extremity dominance: cerebellar hypoplasia associated with a novel mutation in <i><scp>BICD</scp>2</i>

Fiorillo, Chiara; Moro, Francesca; Brisca, Giacomo; Accogli, Andrea; Trucco, Federica; Trovato, Rosanna; Pedemonte, Marina; Severino, Mariasavina; Catala, Martin; Capra, Valeria; Santorelli, Filippo M.; Bruno, Claudio; Rossi, Andrea; Minetti, Carlo

doi:10.1111/ene.12914

Cited by 20 publications

(18 citation statements)

References 7 publications

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“…Studies in rodents have shown that this protein plays an important role in dynein-based cargo transport in neurons (32)(33)(34). Consistent with these findings, missense mutations in the human BICD2 gene are also associated with SMALED (35)(36)(37) and cortical malformations (38,39). The protein uses an N-terminal coiled-coil domain (BICD2N) to bind dynein and dynactin and a C-terminal coiled coil (BICD2C) to bind cargos (17).…”

Section: Significancementioning

confidence: 86%

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

Hoang

Schlager

Carter

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

112

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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 toward 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 characterize 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 Bicaudal-D2 (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 cargos 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. dynein | DYNC1H1 | neurological disease | cargo adaptor | processivity

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Section: Significancementioning

confidence: 86%

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

Hoang

Schlager

Carter

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

112

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“…Another de novo BICD2 mutation p.(Leu683Arg) has been found to cause SMALED2 plus cerebellar hypoplasia. 18 The understanding of the BICD2-related pathomechanism is very limited at present and the localization of the disease-causing mutations along the protein does not seem to be in correlation with the phenotypical presentation and severity of disease. The BICD2 mutation p.(Gln194Arg) identified in the Norwegian individual localizes to the N-terminal coiled-coil 1 (CC1) domain.…”

Section: Discussionmentioning

confidence: 99%

“…19 The lower panel represents disease-causing variants in BICD2 on cDNA and protein level. [1][2][3][4][5][6]11,18 Boxed variants are subject of this work. CC, coiled-coil domain; aa, amino acid; HC, heavy chain.…”

Section: Discussionmentioning

confidence: 99%

Phenotypic extremes of BICD2-opathies: from lethal, congenital muscular atrophy with arthrogryposis to asymptomatic with subclinical features

et al. 2017

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Heterozygous variants in BICD cargo adapter 2 (BICD2) cause autosomal dominant spinal muscular atrophy, lower extremity-predominant 2 (SMALED2). The disease is usually characterized by a benign or slowly progressive, congenital or early onset muscle weakness and atrophy that mainly affects the lower extremities, although some affected individuals show involvement of the arms and the shoulder girdle. Here we report unusual extremes of BICD2-related diseases: A severe form of congenital muscular atrophy with arthrogryposis multiplex, respiratory insufficiency and lethality within four months. This was caused by three BICD2 variants, (c.581A>G, p.(Gln194Arg)), (c.1626C>G, p.(Cys542Trp)) and (c.2080C>T, p.(Arg694Cys)), two of which were proven to be de novo. Affected individuals showed reduced fetal movement, weak muscle tone and sparse or no spontaneous activity after birth. Despite assisted ventilation, the condition led to early death. At the other extreme, we identified an asymptomatic woman with a known BICD2 variant (c.2108C>T, p.(Thr703Met)). Radiological examination showed fatty degeneration of selected thigh and calf muscles without clinical consequences. Instead, her son carrying the same variant is affected by a mild childhood onset disease with myopathic and neurogenic features. Mechanisms leading to variable expressivity and onset of BICD2-related disease may include alterations in molecular interactions of BICD2 and suggest the presence of genetic modifiers that may act in a protective fashion to ameliorate or abrogate disease. Our data define an additional severe disease type caused by BICD2 and emphasize a possibly variable etiology of BICD2-opathies with regard to primary muscle and neuronal involvement.

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“…All affected individuals had weakness predominantly in the lower extremities, usually involving both proximal and distal muscle groups. Additional case reports over the next 2 years [14][15][16][17][18] continued to broaden the mutational and phenotypic spectrum of SMALED2.…”

mentioning

confidence: 99%

The Genotypic and Phenotypic Spectrum of BICD2 Variants in Spinal Muscular Atrophy

Koboldt

Waldrop

Wilson

et al. 2020

Annals of Neurology

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The bicaudal D cargo adaptor 2 (BICD2) gene encodes a conserved cargo adaptor protein required for dynein‐mediated transport. Inherited and de novo variants in BICD2 cause SMALED2 (spinal muscular atrophy lower extremity dominant 2), and a subset have recently been reported to cause severe, often lethal disease. However, a true genotype–phenotype correlation for BICD2 has not been performed, and cases described to date are scattered among at least 14 publications. In this review, we identify the characteristics of disease‐causing variants in BICD2 that distinguish them from benign variation and perform genotype–phenotype correlations for 99 BICD2 variant carriers from 35 families. ANN NEUROL 2020;87:487–496

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Beyond spinal muscular atrophy with lower extremity dominance: cerebellar hypoplasia associated with a novel mutation in BICD2

Cited by 20 publications

References 7 publications

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

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

Phenotypic extremes of BICD2-opathies: from lethal, congenital muscular atrophy with arthrogryposis to asymptomatic with subclinical features

The Genotypic and Phenotypic Spectrum of BICD2 Variants in Spinal Muscular Atrophy

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