Expanding the phenotype of
            <i>BICD2</i>
            mutations toward skeletal muscle involvement

Unger, Andreas; Dekomien, Gabriele; Güttsches, A.; Dreps, Thomas; Kley, Rudolf A.; Tegenthoff, Martin; Ferbert, A.; Weis, Joachim; Heyer, C. M.; Linke, Wolfgang A.; Martinez-Carrera, Lilian A.; Storbeck, Markus; Wirth, Brunhilde; Hoffjan, Sabine; Vorgerd, Matthias

doi:10.1212/wnl.0000000000003360

Cited by 30 publications

(35 citation statements)

References 29 publications

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“…RAB6A staining with confocal microscopy in patient muscle cells revealed a much larger and plane‐wide RAB6A/Golgi‐ER interface. Localization studies indicate that mutant BICD2 aggregates into clusters dotted along the perinuclear region . The authors of this study suggested that the higher Golgi fragmentation correlates with a more severe clinical course, as patients with p.(T703M) variants had the added phenotype of congenital contractures .…”

Section: Discussionmentioning

confidence: 72%

“…Coimmunoprecipitation experiments indicate that this variant also increases BICD2–dynein interaction, seemingly a gain‐of‐function effect. However, localization studies revealed that whereas wild‐type BICD2 localizes to the Golgi apparatus, vesicles, and microtubular filaments in the perinuclear region, mutated BICD2 accumulates in dense clusters near (or even inside) the nucleus . These aggregates appear to cluster at the microtubule organization center (MTOC), to which dynein‐mediated transport is directed.…”

Section: Discussionmentioning

confidence: 99%

“…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%

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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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Section: Discussionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

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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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“…Some patients with MRD13 show clinical evidence of peripheral neuropathy [57]. More recently, BICD2 variant syndrome includes arthrogryposis multiplex congenital with bilateral perisylvian polymicrogyria and a phenotype with chronic myopathy [58, 59]. …”

Section: Sma Plus Syndromesmentioning

confidence: 99%

Inherited Paediatric Motor Neuron Disorders: Beyond Spinal Muscular Atrophy

et al. 2017

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Paediatric motor neuron diseases encompass a group of neurodegenerative diseases characterised by the onset of muscle weakness and atrophy before the age of 18 years, attributable to motor neuron loss across various neuronal networks in the brain and spinal cord. While the genetic underpinnings are diverse, advances in next generation sequencing have transformed diagnostic paradigms. This has reinforced the clinical phenotyping and molecular genetic expertise required to navigate the complexities of such diagnoses. In turn, improved genetic technology and subsequent gene identification have enabled further insights into the mechanisms of motor neuron degeneration and how these diseases form part of a neurodegenerative disorder spectrum. Common pathophysiologies include abnormalities in axonal architecture and function, RNA processing, and protein quality control. This review incorporates an overview of the clinical manifestations, genetics, and pathophysiology of inherited paediatric motor neuron disorders beyond classic SMN1-related spinal muscular atrophy and describes recent advances in next generation sequencing and its clinical application. Specific disease-modifying treatment is becoming a clinical reality in some disorders of the motor neuron highlighting the importance of a timely and specific diagnosis.

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“…It was first suggested that most affected individuals show a similar, recognizable phenotype . However, in recent years, additional phenotypes have been reported for BICD2 mutations, including juvenile amyotrophic lateral sclerosis (ALS), chronic myopathy, and SMA with cerebellar hypoplasia . Further, de‐novo mutations were reported as causative for severe congenital arthrogryposis, and asymptomatic carriers have been described, suggesting that the phenotypic spectrum may vary substantially …”

mentioning

confidence: 99%

BICD2 mutational analysis in hereditary spastic paraplegia and hereditary motor and sensory neuropathy

et al. 2018

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Introduction: Mutations in the BICD2 gene are causative for an autosomal dominant form of spinal muscular atrophy (SMALED2). Further, BICD2 mutations have been implicated in hereditary spastic paraplegia (HSP), but only very few such patients have been described. In this report we aimed to investigate the frequency of BICD2 mutations in patients with HSP and hereditary motor and sensory neuropathy (HMSN) who were negative for the most common known genetic causes. Methods: The cohorts comprised 171 HSP and 189 HMSN patients. Mutational analysis was performed with high‐resolution melting analysis followed by Sanger sequencing. Results: In both cohorts, we found no known or likely pathogenic mutations in the BICD2 gene. Discussion: BICD2 mutations appear rather unlikely to cause a phenotype of HMSN and are a very rare cause of the HSP phenotype. Muscle Nerve 59:484–486, 2019

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Expanding the phenotype of BICD2 mutations toward skeletal muscle involvement

Abstract: Our findings extend the phenotypic spectrum of BICD2-associated disorders by features of a chronic myopathy and show a pathomechanism of BICD2 defects in skeletal muscle.

Cited by 30 publications

References 29 publications

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

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

Inherited Paediatric Motor Neuron Disorders: Beyond Spinal Muscular Atrophy

BICD2 mutational analysis in hereditary spastic paraplegia and hereditary motor and sensory neuropathy

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