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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.

Background Heterozygous variants in BICD2 cause autosomal dominant spinal muscular atrophy with lower extremity predominance. These variants are also identified in individuals with severe forms of congenital muscle atrophy representing arthrogryposis multiplex. Case report A girl was born with severe muscle weakness and respiratory distress. A fetal ultrasound had detected polyhydramnios and multiple joint contractures in utero. She was born with severe muscle weakness and respiratory distress. Bilateral hip joint dislocation and multiple bone fractures were also present at birth. Although she depends on medical care, including assisted ventilation and tube feeding, she has reached eight years of age. Her motor developmental skills were reduced owing to muscle weakness and deformity of her lower extremities, whereas her cognitive development slowly but steadily grew. Whole exome sequencing revealed a novel de novo missense BICD2 variant (c.1625G > A, p.(Cys542Tyr)), which was evaluated as likely pathogenic. Conclusion This is the first case report of a severe form of spinal muscular atrophy with lower extremity predominance caused by a de novo BICD2 variant in Japan.

Heterozygous variants in the bicaudal D homolog 2 gene (BICD2) are associated with autosomal dominant spinal muscular atrophy with lower extremity predominance (SMALED2). This disease is usually characterized by congenital or early-onset muscle weakness and atrophy of the lower extremities with benign or slow progression. We herein described an autosomal dominant inherited pedigree with SMALED2 in which the affected individuals presented with late adult-onset muscle weakness and wasting in the lower extremities. Obviously asymmetrical involvement of the lower limbs was observed in 3 individuals. Muscle magnetic resonance imaging revealed considerable fatty infiltrations in the middle compartment of the lower legs, including the soleus and tibialis posterior muscles. Muscle biopsy samples displayed a neurogenic pattern, but some chronic myopathy-like features were also observed. A novel heterozygous missense mutation (c.361C>G) was identified in a highly-conserved motif of BICD2. Patients with SMALED2 can present with late adult-onset and asymmetrical involvement of the lower limbs. The present study expands the clinical and mutational spectrum of SMALED2.

Introduction Heterozygous BICD2 gene mutations cause a form of autosomal dominant spinal muscular atrophy with lower extremity predominance (SMALED). Methods We analyzed the BICD2 gene in a selected group of 25 index patients with neurogenic muscle atrophy. Results We identified 2 new BICD2 missense mutations, c.2515G>A, p.Gly839Arg, in a family with autosomal dominant inheritance, and c.2202G>T, p.Lys734Asn, as a de novo mutation in an isolated patient with similar phenotype. The patients had congenital foot contractures, muscle atrophy of the legs, and slowly progressive weakness of the shoulder girdle. There was no apparent sensory or brain dysfunction. One patient died of unrelated reasons at age 52 years. Autopsy revealed no upper motor neuron and only moderate lower motor neuron loss, but there was distal corticospinal tract degeneration and marked neurogenic muscular atrophy. Conclusion These findings give further insight into the clinical and pathoanatomical consequences of BICD2 mutations. Muscle Nerve 54: 496–500, 2016

Item does not contain fulltext We describe four unrelated patients with the same de novo heterozygous missense mutation c.751C>T in the DYNC1H1 gene. We found a high phenotype-genotype correlation with all four patients having early childhood-onset predominant lower limb muscle weakness and wasting which was slowly progressing and later-onset mild upper extremities proximal weakness. All four patients presented minor cognitive dysfunction with learning difficulty and developmental behavioural comorbidities with mild abnormalities in the brain MRI. The leg muscle MRI findings are highly consistent in DYN1CH1-related spinal muscular atrophy with lower limb predominance (SMALED) with relative sparing of biceps femoris and semitendinosus, and hypertrophy of adductor longus in the thighs; and sparing the anterior and medial muscles in the calves. This report provides important clinical evidence indicating the de novo heterozygous missense mutation c.751C>T in the DYNC1H1 gene is pathogenic causing SMALED. Muscle MRI is more specific than muscle biopsy in the diagnosis of SMALED.

Background Molecular diagnosis of the distal spinal muscular atrophies or distal hereditary motor neuropathies remains challenging because of clinical and genetic heterogeneity. Next generation sequencing offers potential for identifying de novo mutations of causative genes in isolated cases. Patient Description We present a 3.6-year-old girl with congenital scoliosis, equinovarus, and L5/S1 left hemivertebra who demonstrated delayed walking and lower extremities atrophy. She was negative for SMN1 deletion testing, and parents show no sign of disease. Results Whole exome sequencing of the affected girl showed a novel de novo heterozygous missense mutation c.1792C>T (p.Arg598Cys) in the tail domain of the DYNC1H1 gene encoding for cytoplasmic dynein heavy chain 1. The mutation changed a highly conserved amino acid and was absent from both parents. Conclusion De novo mutations of DYNC1H1 have been found in individuals with autosomal dominant mental retardation with neuronal migration defects. Dominantly inherited mutations of DYNC1H1 have been reported to cause spinal muscular atrophy with predominance of lower extremity involvement and Charcot-Marie-Tooth type 2O. This is the first report of a de novo DYNC1H1 mutation associated with the spinal muscular atrophy with predominance of lower extremity phenotype with a spinal deformity (lumbar hemivertebrae). This case also demonstrates the power of next generation sequencing to discover de novo mutations on a genome-wide scale.

Exome sequencing has become a formidable tool for identifying potential de novo variants in causative genes of human diseases, such as neurodegenerative disorders. This article describes a 16-month-old girl with spinal muscular atrophy with lower extremity predominance and a 13-month-old girl with malformations of cortical development. Exome sequencing identified a novel de novo heterozygous missense mutation c.3395G>A (p.Gly1132Glu) and a previously reported de novo heterozygous missense mutation c.10151G>A (p.Arg3384Gln) in the DYNC1H1 gene. Bioinformatics predictions for c.3395G>A and c.10151G>A indicated pathogenicity of the mutations. DYNC1H1 is a pivotal component of cytoplasmic dynein complex, which is a microtubule-related motor involved in retrograde transport. Previous studies indicated that mutant dynein showed decreased run-length of the motor proteins and diminished retrograde transport, which were clearly associated with neuronal death and neurologic diseases. The present findings expand the mutational spectrum of the DYNC1H1 gene, reemphasizing the significance of the DYNC1H1 protein in the functioning of neurons.

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.

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.

Objective:To expand the spectrum of bicaudal D, Drosophila, homologue 2 (BICD2) gene–related diseases, which so far includes autosomal dominant spinal muscular atrophy with lower extremity predominance 2 and hereditary spastic paraplegia due to mutations in the BICD2 gene.Methods:We analyzed 2 independent German families with clinical, genetic, and muscle MRI studies. In both index patients, muscle histopathologic studies were performed. Transfection studies were carried out to analyze the functional consequences of the disease-causing mutations.Results:We identified the mutations p.Ser107Leu and p.Thr703Met in the BICD2 gene in the 2 families, respectively. In contrast to other patients carrying the same mutations, our patients present features of a myopathy with slow progression. Immunofluorescence studies and immunoelectron microscopy showed striking impairment of Golgi integrity, vesicle pathology, and abnormal BICD2 accumulation either within the nuclei (p.Ser107Leu) or in the perinuclear region (p.Thr703Met). Transfection studies confirmed BICD2 aggregation in different subcellular locations.Conclusions: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.

Objective: Spinal muscular atrophies (SMAs) are hereditary disorders characterized by weakness from degeneration of spinal motor neurons. Although most SMA cases with proximal weakness are recessively inherited, rare families with dominant inheritance have been reported. We aimed to clinically, pathologically, and genetically characterize a large North American family with an autosomal dominant proximal SMA. Methods: Affected family members underwent clinical and electrophysiologic evaluation. Twenty family members were genotyped on high-density genome-wide SNP arrays and linkage analysis was performed. Results: Ten affected individuals (ages 7–58 years) showed prominent quadriceps atrophy, moderate to severe weakness of quadriceps and hip abductors, and milder degrees of weakness in other leg muscles. Upper extremity strength and sensation was normal. Leg weakness was evident from early childhood and was static or very slowly progressive. Electrophysiology and muscle biopsies were consistent with chronic denervation. SNP-based linkage analysis showed a maximum 2-point lod score of 5.10 (θ = 0.00) at rs17679127 on 14q32. A disease-associated haplotype spanning from 114 cM to the 14q telomere was identified. A single recombination narrowed the minimal genomic interval to Chr14: 100,220,765–106,368,585. No segregating copy number variations were found within the disease interval. Conclusions: We describe a family with an early onset, autosomal dominant, proximal SMA with a distinctive phenotype: symptoms are limited to the legs and there is notable selectivity for the quadriceps. We demonstrate linkage to a 6.1-Mb interval on 14q32 and propose calling this disorder spinal muscular atrophy–lower extremity, dominant.

Recent studies have identified mutations in the dynein heavy chain gene (DYNC1H1), which lead to 2 closely related human motor neuropathies: a dominant spinal muscular atrophy with lower extremity predominance (SMALED) and axonal Charcot-Marie-Tooth (CMT) disease.(1,2) We describe the identification of a novel mutation (p.G807S) in DYNC1H1 as the cause of SMALED.

OBJECTIVE\ud \ud To expand the clinical phenotype of autosomal dominant congenital spinal muscular atrophy with lower extremity predominance (SMA-LED) due to mutations in the dynein, cytoplasmic 1, heavy chain 1 (DYNC1H1) gene.\ud \ud METHODS\ud \ud Patients with a phenotype suggestive of a motor, non-length-dependent neuronopathy predominantly affecting the lower limbs were identified at participating neuromuscular centers and referred for targeted sequencing of DYNC1H1.\ud \ud RESULTS\ud \ud We report a cohort of 30 cases of SMA-LED from 16 families, carrying mutations in the tail and motor domains of DYNC1H1, including 10 novel mutations. These patients are characterized by congenital or childhood-onset lower limb wasting and weakness frequently associated with cognitive impairment. The clinical severity is variable, ranging from generalized arthrogryposis and inability to ambulate to exclusive and mild lower limb weakness. In many individuals with cognitive impairment (9/30 had cognitive impairment) who underwent brain MRI, there was an underlying structural malformation resulting in polymicrogyric appearance. The lower limb muscle MRI shows a distinctive pattern suggestive of denervation characterized by sparing and relative hypertrophy of the adductor longus and semitendinosus muscles at the thigh level, and diffuse involvement with relative sparing of the anterior-medial muscles at the calf level. Proximal muscle histopathology did not always show classic neurogenic features.\ud \ud CONCLUSION\ud \ud Our report expands the clinical spectrum of DYNC1H1-related SMA-LED to include generalized arthrogryposis. In addition, we report that the neurogenic peripheral pathology and the CNS neuronal migration defects are often associated, reinforcing the importance of DYNC1H1 in both central and peripheral neuronal functions.

Mutations in the gene encoding the heavy chain subunit (DYNC1H1) of cytoplasmic dynein cause spinal muscular atrophy with lower extremity predominance, Charcot-Marie-Tooth disease and intellectual disability. We used the legs at odd angles (Loa) (DYNC1H1(F580Y)) mouse model for spinal muscular atrophy with lower extremity predominance and a combination of live-cell imaging and biochemical assays to show that the velocity of dynein-dependent microtubule minus-end (towards the nucleus) movement of EGF and BDNF induced signalling endosomes is significantly reduced in Loa embryonic fibroblasts and motor neurons. At the same time, the number of the plus-end (towards the cell periphery) moving endosomes is increased in the mutant cells. As a result, the extracellular signal-regulated kinases (ERK) 1/2 activation and c-Fos expression are altered in both mutant cell types, but the motor neurons exhibit a strikingly abnormal ERK1/2 and c-Fos response to serum-starvation induced stress. These data highlight the cell-type specific ERK1/2 response as a possible contributory factor in the neuropathological nature of Dync1h1 mutations, despite generic aberrant kinetics in both cell types, providing an explanation for how mutations in the ubiquitously expressed DYNC1H1 cause neuron-specific disease.

Mutations in the DYNC1H1 gene encoding for dynein heavy chain cause two closely related human motor neuropathies, dominant spinal muscular atrophy with lower extremity predominance (SMA-LED) and axonal Charcot-Marie-Tooth (CMT) disease, and lead to sensory neuropathy and striatal atrophy in mutant mice. Dynein is the molecular motor carrying mitochondria retrogradely on microtubules, yet the consequences of dynein mutations on mitochondrial physiology have not been explored. Here, we show that mouse fibroblasts bearing heterozygous or homozygous point mutation in Dync1h1, similar to human mutations, show profoundly abnormal mitochondrial morphology associated with the loss of mitofusin 1. Furthermore, heterozygous Dync1h1 mutant mice display progressive mitochondrial dysfunction in muscle and mitochondria progressively increase in size and invade sarcomeres. As a likely consequence of systemic mitochondrial dysfunction, Dync1h1 mutant mice develop hyperinsulinemia and hyperglycemia and progress to glucose intolerance with age. Similar defects in mitochondrial morphology and mitofusin levels are observed in fibroblasts from patients with SMA-LED. Last, we show that Dync1h1 mutant fibroblasts show impaired perinuclear clustering of mitochondria in response to mitochondrial uncoupling. Our results show that dynein function is required for the maintenance of mitochondrial morphology and function with aging and suggest that mitochondrial dysfunction contributes to dynein-dependent neurological diseases, such as SMA-LED.

Objective: To identify the gene responsible for 14q32-linked dominant spinal muscular atrophy with lower extremity predominance (SMA-LED, OMIM 158600). Methods: Target exon capture and next generation sequencing was used to analyze the 73 genes in the 14q32 linkage interval in 3 SMA-LED family members. Candidate gene sequencing in additional dominant SMA families used PCR and pooled target capture methods. Patient fibroblasts were biochemically analyzed. Results: Regional exome sequencing of all candidate genes in the 14q32 interval in the original SMA-LED family identified only one missense mutation that segregated with disease state—a mutation in the tail domain of DYNC1H1 (I584L). Sequencing of DYNC1H1 in 32 additional probands with lower extremity predominant SMA found 2 additional heterozygous tail domain mutations (K671E and Y970C), confirming that multiple different mutations in the same domain can cause a similar phenotype. Biochemical analysis of dynein purified from patient-derived fibroblasts demonstrated that the I584L mutation dominantly disrupted dynein complex stability and function. Conclusions: We demonstrate that mutations in the tail domain of the heavy chain of cytoplasmic dynein ( DYNC1H1 ) cause spinal muscular atrophy and provide experimental evidence that a human DYNC1H1 mutation disrupts dynein complex assembly and function. DYNC1H1 mutations were recently found in a family with Charcot-Marie-Tooth disease (type 2O) and in a child with mental retardation. Both of these phenotypes show partial overlap with the spinal muscular atrophy patients described here, indicating that dynein dysfunction is associated with a range of phenotypes in humans involving neuronal development and maintenance.

Whole-exome sequencing of two affected sibs and their mother who showed a unique quadriceps-dominant form of neurogenic muscular atrophy disclosed a heterozygous DYNC1H1 mutation [p.H306R (c.917A>G)]. The identical mutation was recently reported in a pedigree with the axonal form of Charcot–Marie–Tooth disease. Three other missense mutations in DYNC1H1 were also identified in families with dominant spinal muscular atrophy with lower extremity predominance. Their clinical features were consistent with those of our family. Our study has demonstrated that the same DYNC1H1 mutation could cause spinal muscular atrophy as well as distal neuropathy, indicating pleotropic effects of the mutation.