The p.Ser107Leu in BICD2 is a mutation 'hot spot' causing distal spinal muscular atrophy.
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ABSTRACT:
SUBMITTER: Bansagi B
PROVIDER: S-EPMC4620510 | biostudies-literature | 2015 Nov
REPOSITORIES: biostudies-literature
Publications
The p.Ser107Leu in BICD2 is a mutation 'hot spot' causing distal spinal muscular atrophy.
Bansagi Boglarka B Griffin Helen H Ramesh Venkateswaran V Duff Jennifer J Pyle Angela A Chinnery Patrick F PF Horvath Rita R
Brain : a journal of neurology 20150610 Pt 11
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Project description:The bicaudal D homolog 2 (BICD2) gene encodes a protein required for the stable complex of dynein and dynactin, which functions as a motor protein working along the microtubule cytoskeleton. Both inherited and de novo variants of BICD2 are reported with autosomal dominant spinal muscular atrophy with lower extremity predominance (SMALED2). Here, we report a male patient with a novel mutation in the BICD2 gene caused by a heterozygous substitution of arginine with cysteine at residue 162 (Arg162Cys); inherited from his asymptomatic mother. The patient showed typical clinical symptoms of SMALED2, which was genetically confirmed by sequencing. The Arg162Cys mutant clusters with four previously reported variants (c.361C>G, p.Leu121Val; c.581A>G, p.Gln194Arg; c.320C>T, p.Ser107Leu; c.565A>T, p.Ile189Phe) in a region that binds to the dynein-dynactin complex (DDC). The BICD2 domain structures were predicted and the Arg162Cys mutation was localized in the N-terminus coiled-coil segment 1 (CC1) domain. Protein modeling of BICD2's CC1 domain predicted that the Arg162Cys missense variant disrupted interactions with dynein cytoplasmic 1 heavy chain 1 within the DDC. The mutant did this by either changing the electrostatic surface potential or making a broader hydrophobic unit with the neighboring residues. This hereditary case supports the complex and broad genotype-phenotype correlation of BICD2 mutations, which could be explained by incomplete penetrance or variable expressivity in the next generation.
| S-EPMC8122317 | biostudies-literature
Project description:Spinal muscular atrophies (SMAs) are a heterogeneous group of inherited disorders characterized by degeneration of anterior horn cells and progressive muscle weakness. In two unrelated families affected by a distinct form of autosomal-dominant distal SMA initially manifesting with calf weakness, we identified by genetic linkage analysis and exome sequencing a heterozygous missense mutation, c.616T>C (p.Cys206Arg), in F-box protein 38 (FBXO38). FBXO38 is a known coactivator of the transcription factor Krüppel-like factor 7 (KLF7), which regulates genes required for neuronal axon outgrowth and repair. The p.Cys206Arg substitution did not alter the subcellular localization of FBXO38 but did impair KLF7-mediated transactivation of a KLF7-responsive promoter construct and endogenous KLF7 target genes in both heterologously expressing human embryonic kidney 293T cells and fibroblasts derived from individuals with the FBXO38 missense mutation. This transcriptional dysregulation was associated with an impairment of neurite outgrowth in primary motor neurons. Together, these results suggest that a transcriptional regulatory pathway that has a well-established role in axonal development could also be critical for neuronal maintenance and highlight the importance of FBXO38 and KLF7 activity in motor neurons.
| S-EPMC3824115 | biostudies-literature
Project description:ObjectiveTo identify the genetic cause of disease in a form of congenital spinal muscular atrophy and arthrogryposis (CSMAA).MethodsA 2-year-old boy was diagnosed with arthrogryposis multiplex congenita, severe skeletal abnormalities, torticollis, vocal cord paralysis, and diminished lower limb movement. Whole-exome sequencing (WES) was performed on the proband and family members. In silico modeling of protein structure and heterologous protein expression and cytotoxicity assays were performed to validate pathogenicity of the identified variant.ResultsWES revealed a homozygous mutation in the TRPV4 gene (c.281C>T; p.S94L). The identification of a recessive mutation in TRPV4 extends the spectrum of mutations in recessive forms of the TRPV4-associated disease. p.S94L and other previously identified TRPV4 variants in different protein domains were compared in structural modeling and functional studies. In silico structural modeling suggests that the p.S94L mutation is in the disordered N-terminal region proximal to important regulatory binding sites for phosphoinositides and for PACSIN3, which could lead to alterations in trafficking and/or channel sensitivity. Functional studies by Western blot and immunohistochemical analysis show that p.S94L increased TRPV4 activity-based cytotoxicity and resultant decreased TRPV4 expression levels, therefore involves a gain-of-function mechanism.ConclusionsThis study identifies a novel homozygous mutation in TRPV4 as a cause of the recessive form of CSMAA.
| S-EPMC6454305 | biostudies-literature
Project description:Dominant congenital spinal muscular atrophy (DCSMA) is a disorder of developing anterior horn cells and shows lower-limb predominance and clinical overlap with hereditary spastic paraplegia (HSP), a lower-limb-predominant disorder of corticospinal motor neurons. We have identified four mutations in bicaudal D homolog 2 (Drosophila) (BICD2) in six kindreds affected by DCSMA, DCSMA with upper motor neuron features, or HSP. BICD2 encodes BICD2, a key adaptor protein that interacts with the dynein-dynactin motor complex, which facilitates trafficking of cellular cargos that are critical to motor neuron development and maintenance. We demonstrate that mutations resulting in amino acid substitutions in two binding regions of BICD2 increase its binding affinity for the cytoplasmic dynein-dynactin complex, which might result in the perturbation of BICD2-dynein-dynactin-mediated trafficking, and impair neurite outgrowth. These findings provide insight into the mechanism underlying both the static and the slowly progressive clinical features and the motor neuron pathology that characterize BICD2-associated diseases, and underscore the importance of the dynein-dynactin transport pathway in the development and survival of both lower and upper motor neurons.
| S-EPMC3675232 | biostudies-literature
Project description:Spinal muscular atrophy is a disorder of lower motor neurons, most commonly caused by recessive mutations in SMN1 on chromosome 5q. Cases without SMN1 mutations are subclassified according to phenotype. Spinal muscular atrophy, lower extremity-predominant, is characterized by lower limb muscle weakness and wasting, associated with reduced numbers of lumbar motor neurons and is caused by mutations in DYNC1H1, which encodes a microtubule motor protein in the dynein-dynactin complex and one of its cargo adaptors, BICD2. We have now identified 32 patients with BICD2 mutations from nine different families, providing detailed insights into the clinical phenotype and natural history of BICD2 disease. BICD2 spinal muscular atrophy, lower extremity predominant most commonly presents with delayed motor milestones and ankle contractures. Additional features at presentation include arthrogryposis and congenital dislocation of the hips. In all affected individuals, weakness and wasting is lower-limb predominant, and typically involves both proximal and distal muscle groups. There is no evidence of sensory nerve involvement. Upper motor neuron signs are a prominent feature in a subset of individuals, including one family with exclusively adult-onset upper motor neuron features, consistent with a diagnosis of hereditary spastic paraplegia. In all cohort members, lower motor neuron features were static or only slowly progressive, and the majority remained ambulant throughout life. Muscle MRI in six individuals showed a common pattern of muscle involvement with fat deposition in most thigh muscles, but sparing of the adductors and semitendinosus. Muscle pathology findings were highly variable and included pseudomyopathic features, neuropathic features, and minimal change. The six causative mutations, including one not previously reported, result in amino acid changes within all three coiled-coil domains of the BICD2 protein, and include a possible 'hot spot' mutation, p.Ser107Leu present in four families. We used the recently solved crystal structure of a highly conserved region of the Drosophila orthologue of BICD2 to further-explore how the p.Glu774Gly substitution inhibits the binding of BICD2 to Rab6. Overall, the features of BICD2 spinal muscular atrophy, lower extremity predominant are consistent with a pathological process that preferentially affects lumbar lower motor neurons, with or without additional upper motor neuron involvement. Defining the phenotypic features in this, the largest BICD2 disease cohort reported to date, will facilitate focused genetic testing and filtering of next generation sequencing-derived variants in cases with similar features.
| S-EPMC4306822 | biostudies-literature
Project description:Spinal muscular atrophies (SMAs) are characterized by degeneration of spinal motor neurons and muscle weakness. Autosomal recessive SMA is the most common form and is caused by homozygous deletions/mutations of the SMN1 gene. However, families with dominant inherited SMA have been reported, for most of them the causal gene remains unknown. Recently, we and others have identified heterozygous mutations in BICD2 as causative for autosomal dominant SMA, lower extremity-predominant, 2 (SMALED2) and hereditary spastic paraplegia (HSP). BICD2 encodes the Bicaudal D2 protein, which is considered to be a golgin, due to its coiled-coil (CC) structure and interaction with the small GTPase RAB6A located at the Golgi apparatus. Golgins are resident proteins in the Golgi apparatus and form a matrix that helps to maintain the structure of this organelle. Golgins are also involved in the regulation of vesicle transport. In vitro overexpression experiments and studies of fibroblast cell lines derived from patients, showed fragmentation of the Golgi apparatus. In the current review, we will discuss possible causes for this disruption, and the consequences at cellular level, with a view to better understand the pathomechanism of this disease.
| S-EPMC4633519 | biostudies-literature
Project description:The most common form of spinal muscular atrophy (SMA) is a recessive disorder caused by deleterious SMN1 mutations in 5q13, whereas the genetic etiologies of non-5q SMA are very heterogeneous and largely remain to be elucidated. In a Bulgarian family affected by autosomal-dominant proximal SMA, we performed genome-wide linkage analysis and whole-exome sequencing and found a heterozygous de novo c.320C>T (p.Ser107Leu) mutation in bicaudal D homolog 2 (Drosophila) (BICD2). Further analysis of BICD2 in a cohort of 119 individuals with non-5q SMA identified a second de novo BICD2 mutation, c.2321A>G (p.Glu774Gly), in a simplex case. Detailed clinical and electrophysiological investigations revealed that both families are affected by a very similar disease course, characterized by early childhood onset, predominant involvement of lower extremities, and very slow disease progression. The amino acid substitutions are located in two interaction domains of BICD2, an adaptor protein linking the dynein molecular motor with its cargo. Our immunoprecipitation and localization experiments in HeLa and SH-SY5Y cells and affected individuals' lymphoblasts demonstrated that p.Ser107Leu causes increased dynein binding and thus leads to accumulation of BICD2 at the microtubule-organizing complex and Golgi fragmentation. In addition, the altered protein had a reduced colocalization with RAB6A, a regulator of vesicle trafficking between the Golgi and the endoplasmic reticulum. The interaction between p.Glu744Gly altered BICD2 and RAB6A was impaired, which also led to their reduced colocalization. Our study identifies BICD2 mutations as a cause of non-5q linked SMA and highlights the importance of dynein-mediated motility in motor neuron function in humans.
| S-EPMC3675262 | biostudies-literature
Project description:Autosomal dominant missense mutations in BICD2 cause Spinal Muscular Atrophy Lower Extremity Predominant 2 (SMALED2), a developmental disease of motor neurons. BICD2 is a key component of the cytoplasmic dynein/dynactin motor complex, which in axons drives the microtubule-dependent retrograde transport of intracellular cargo towards the cell soma. Patients with pathological mutations in BICD2 develop malformations of cortical and cerebellar development similar to Bicd2 knockout (-/-) mice. In this study we sought to re-examine the motor neuron phenotype of conditional Bicd2-/- mice. Bicd2-/- mice show a significant reduction in the number of large calibre motor neurons of the L4 ventral root compared to wild type mice. Muscle-specific knockout of Bicd2 results in a similar reduction in L4 ventral axons comparable to global Bicd2-/- mice. Rab6, a small GTPase required for the sorting of exocytic vesicles from the Trans Golgi Network to the plasma membrane is a major binding partner of BICD2. We therefore examined the secretory pathway in SMALED2 patient fibroblasts and demonstrated that BICD2 is required for physiological flow of constitutive secretory cargoes from the Trans Golgi Network to the plasma membrane using a VSV-G reporter assay. Together, these data indicate that BICD2 loss from muscles is a major driver of non-cell autonomous pathology in the motor nervous system, which has important implications for future therapeutic approaches in SMALED2.
| S-EPMC7076953 | biostudies-literature
Project description:Spinal muscular atrophy (SMA) is a potentially devastating and lethal neuromuscular disease frequently manifesting in infancy and childhood. The discovery of the underlying mutation in the survival of motor neurons 1 (SMN1) gene has accelerated preclinical research, leading to treatment targets and transgenic mouse models, but there is still no effective treatment. The clinical severity is inversely related to the copy number of SMN2, a modifying gene producing some full-length SMN transcript. Drugs shown to increase SMN2 function in vitro, therefore, have the potential to benefit patients with SMA. Because several drugs are now on the horizon of clinical investigation, we review recent clinical trials for SMA and discuss the challenges and opportunities associated with SMA drug development. Although an orphan disease, SMA is well-positioned for successful trials given that it has a common genetic etiology in most cases, that it can be readily diagnosed, that preclinical research in vitro and in transgenic animals has identified candidate compounds, and that trial networks have been established.
| S-EPMC4514700 | biostudies-other
Project description:Tubulinopathies constitute a family of neurodevelopmental/neurodegenerative disorders caused by mutations in several genes encoding tubulin isoforms. Loss-of-function mutations in TBCE, encoding one of the five tubulin-specific chaperones involved in tubulin folding and polymerization, cause two rare neurodevelopmental syndromes, hypoparathyroidism-retardation-dysmorphism and Kenny-Caffey syndrome. Although a missense mutation in Tbce has been associated with progressive distal motor neuronopathy in the pmn/pmn mice, no similar degenerative phenotype has been recognized in humans. We report on the identification of an early-onset and progressive neurodegenerative encephalopathy with distal spinal muscular atrophy resembling the phenotype of pmn/pmn mice and caused by biallelic TBCE mutations, with the c.464T>A (p.Ile155Asn) change occurring at the heterozygous/homozygous state in six affected subjects from four unrelated families originated from the same geographical area in Southern Italy. Western blot analysis of patient fibroblasts documented a reduced amount of TBCE, suggestive of rapid degradation of the mutant protein, similarly to what was observed in pmn/pmn fibroblasts. The impact of TBCE mutations on microtubule polymerization was determined using biochemical fractionation and analyzing the nucleation and growth of microtubules at the centrosome and extracentrosomal sites after treatment with nocodazole. Primary fibroblasts obtained from affected subjects displayed a reduced level of polymerized α-tubulin, similarly to tail fibroblasts of pmn/pmn mice. Moreover, markedly delayed microtubule re-polymerization and abnormal mitotic spindles with disorganized microtubule arrangement were also documented. Although loss of function of TBCE has been documented to impact multiple developmental processes, the present findings provide evidence that hypomorphic TBCE mutations primarily drive neurodegeneration.
| S-EPMC5065657 | biostudies-literature