BICD2

BICD2 variants have been linked to neurodegenerative disorders like spinal muscular atrophy with lower extremity predominance (SMALED2) or hereditary spastic paraplegia (HSP). Recently, mutations in BICD2 were implicated in myopathies. Here, we present one patient with a known and six patients with novel BICD2 missense variants, further characterizing the molecular landscape of this heterogenous neurological disorder. A total of seven patients were genotyped and phenotyped. Skeletal muscle biopsies were analyzed by histology, electron microscopy, and protein profiling to define pathological hallmarks and pathogenicity markers with consecutive validation using fluorescence microscopy...

Bicaudal D2 (BICD2) is responsible for recruiting cytoplasmic dynein to diverse forms of subcellular cargo for their intracellular transport. Mutations in the human BICD2 gene have been found to cause an autosomal dominant form of spinal muscular atrophy (SMA-LED2), and brain developmental defects. Whether and how the latter mutations are related to roles we and others have identified for BICD2 in brain development remains little understood. BICD2 interacts with the nucleoporin RanBP2 to recruit dynein to the nuclear envelope (NE) of Radial Glial Progenitor cells (RGPs) to mediate their well-known but mysterious cell-cycle-regulated interkinetic nuclear migration (INM) behavior, and their subsequent differentiation to form cortical neurons...

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The adapter dynactin and the activator BicD2 associate with dynein to form the highly motile dynein-dynactin-BicD2 (DDB) complex. In single-molecule assays, DDB displays processive runs, diffusive episodes, and transient pauses. The switching rates and durations of the different phases can be determined by tracking gold nanoparticle-labeled DDB complexes with interferometric scattering (iSCAT) microscopy and using an algorithm to separate out different motility phases. Here we describe methods for purifying DDB complexes from brain lysate, labeling with gold nanoparticles, imaging by iSCAT, and analyzing the resulting trajectories...

No abstract text is available yet for this article.

Spinal muscular atrophy with lower extremity dominant (SMALED) is a hereditary neuromuscular disorder characterized by degeneration of spinal cord motor neurons resulting in lower limbs muscle weakness and paralysis. Mutations in DYNC1H1, which encodes BICD2, a multifunctional adaptor for microtubule motor proteins, cause the disorder. Here, we generated four induced pluripotent stem cell (iPSC) lines from patients with SMALED. Dermal fibroblasts were obtained from the MRC neuromuscular disease biobank and reprogrammed using non-integrating mRNA-based protocol...

Cargo adaptors are crucial in coupling motor proteins with their respective cargos and regulatory proteins. BicD2 is a prominent example within the cargo adaptor family. BicD2 is able to recruit the microtubule motor dynein to RNA, viral particles, and nuclei. The BicD2-mediated interaction between the nucleus and dynein is implicated in mitosis, interkinetic nuclear migration (INM) in radial glial progenitor cells, and neuron precursor migration during embryonic neocortex development. In vitro studies involving full-length cargo adaptors are difficult to perform due to the hydrophobic character, low-expression levels, and intrinsic flexibility of cargo adaptors...

Hereditary spastic paraplegia (HSP) is among the most genetically diverse of all monogenic diseases. The aim was to analyze the genetic causes of HSP among adult Serbian patients. The study comprised 74 patients from 65 families clinically diagnosed with HSP during a nine-year prospective period. A panel of thirteen genes was analyzed: L1CAM (SPG1), PLP1 (SPG2), ATL1 (SPG3A), SPAST (SPG4), CYP7B1 (SPG5A), SPG7 (SPG7), KIF5A (SPG10), SPG11 (SPG11), ZYFVE26 (SPG15), REEP1 (SPG31), ATP13A2 (SPG78), DYNC1H1, and BICD2 using a next generation sequencing-based technique...

Bidirectional cargo transport in neurons requires competing activity of motors from the kinesin-1, -2 and -3 superfamilies against cytoplasmic dynein-1. Previous studies demonstrated that when kinesin-1 attached to dynein-dynactin-BicD2 (DDB) complex, the tethered motors move slowly with a slight plus-end bias, suggesting kinesin-1 overpowers DDB but DDB generates a substantial hindering load. Compared to kinesin-1, motors from the kinesin-2 and -3 families display a higher sensitivity to load in single-molecule assays and are thus predicted to be overpowered by dynein complexes in cargo transport...

BACKGROUND: Familial dilated cardiomyopathy (DCM) is a genetic cardiomyopathy that is associated with reduced left ventricle function or systolic function. Fifty-one DCM-causative genes have been reported, most of which are inherited in an autosomal dominant manner. However, recessive DCM-causative gene is rarely observed. METHODS: Whole-exome sequencing (WES) was performed in a consanguineous family with DCM to identify candidate variants. Sanger sequencing was utilized to confirm the variant...

This case report describes a girl who presented antenatal arthrogryposis and postnatal hypotonia, generalized and respiratory weakness, joint deformities particularly affecting the lower limbs and poor swallow. By 5 months, cataracts, abnormal electroretinograms, visual evoked potentials and global developmental impairments were recognized. No causative variants were identified on targeted gene panels. After her unexpected death at 11 months, gene-agnostic trio whole exome sequencing revealed a likely pathogenic de novo BICD2 missense variant, NM_001003800...

Tight junctions (TJs) are located in the apical region of the junctions between epithelial cells and are widely found in organs such as the brain, retina, intestinal epithelium, and endothelial system. As a mechanical barrier of the intestinal mucosa, TJs can not only maintain the integrity of intestinal epithelial cells but also maintain intestinal mucosal permeability by regulating the entry of ions and molecules into paracellular channels. Therefore, the formation disorder or integrity destruction of TJs can induce damage to the intestinal epithelial barrier, ultimately leading to the occurrence of various gastrointestinal diseases, such as inflammatory bowel disease (IBD), gastroesophageal reflux disease (GERD), and irritable bowel syndrome (IBS)...

Developmental brain malformations are rare but are increasingly reported features of BICD2-related disorders. Here, we report a 2-year old boy with microcephaly, profound delay and partial seizures. His brain MRI showed lissencephaly, hypogenesis of corpus callosum, dysplastic hipocampus and cerebellar hypoplasia. Whole-exome sequencing identified a novel homozygous likely pathogenic variant in the BICD2 gene, c.229 C > T p.(Gln77Ter). This is the first report of lissencephaly and cerebellar hypoplasia seen in a patient with homozygous loss-of-function variant in BICD2 that recapitulated the animal model...

Major depressive disorder (MDD) is a prevalent and devastating mental illness. To date, the diagnosis of MDD is largely dependent on clinical interviews and questionnaires and still lacks a reliable biomarker. DNA methylation has a stable and reversible nature and is likely associated with the course and therapeutic efficacy of complex diseases, which may play an important role in the etiology of a disease. Here, we identified and validated a DNA methylation biomarker for MDD from four independent cohorts of the Chinese Han population...

Disease-specific autoantibodies are considered the most important biomarkers for systemic sclerosis (SSc), due to their ability to stratify patients with different severity and prognosis. Anti-nuclear antibodies (ANA), occurring in subjects with isolated Raynuad's phenomenon, are considered the strongest independent predictors of definite SSc and digital microvascular damage, as observed by nailfold videocapillaroscopy. ANA are present in more than 90% of SSc, but ANA negativity does not exclude SSc diagnosis: a little rate of SSc ANA negative exists and shows a distinct subtype of disease, with less vasculopathy, but more frequent lower gastrointestinal involvement and severe disease course...

DNA viruses that replicate in the nuclei of infected cells must transport to and deliver their viral genomes into the nucleus to cause infection. How polyomavirus (PyV), a tumor virus that causes debilitating disease in humans, accomplishes this essential step in infection is not well-understood. During entry, PyV sorts from the cell surface to the endoplasmic reticulum (ER) where it penetrates the ER membrane to reach the cytosol. From there, the virus is transported to the nucleus for entry through the narrow nuclear pore complex (NPC)...

INTRODUCTION: Bicaudal D homolog 2 (BICD2) is a causative gene of autosomal-dominant lower extremity-predominant spinal muscular atrophy-2 (SMA-LED2). The severity of SMA-LED2 varies widely, ranging from cases in which patients are able to walk to cases in which severe joint contractures lead to respiratory failure. In this study, we report the long-term course of a case of SMA-LED2 in comparison with previous reports. CASE REPORT: The patient was a 19-year-old woman...

An elderly man in his early 80s presented with a 6-month history of worsening lower limb weakness on a background of a longer-standing waddling gait. Examination revealed bilateral scapular winging, and weakness in his proximal and distal lower limbs. Electromyography showed widespread chronic partial denervation changes, while sensory and motor nerve conduction parameters were preserved. After little progression over the course of 18 months, motor neuron disease was deemed less likely. Genetic testing revealed BICD2-related spinal muscular atrophy with lower extremity dominance (SMALED2), a disease that is usually of earlier onset...