Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1762617 (weakness)
 37,932 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Spinal muscular atrophy (SMA) is a heterogeneous group of neuromuscular disorders caused by degeneration of lower motor neurons. Although functional loss of SMN1 is associated with autosomal-recessive childhood SMA, the genetic cause for most families affected by dominantly inherited SMA is unknown. Here, we identified pathogenic variants in bicaudal D homolog 2 (Drosophila) (BICD2) in three families afflicted with autosomal-dominant SMA. Affected individuals displayed congenital slowly progressive muscle weakness mainly of the lower limbs and congenital contractures. In a large Dutch family, linkage analysis identified a 9q22.3 locus in which exome sequencing uncovered c.320C>T (p.Ser107Leu) in BICD2. Sequencing of 23 additional families affected by dominant SMA led to the identification of pathogenic variants in one family from Canada (c.2108C>T [p.Thr703Met]) and one from the Netherlands (c.563A>C [p.Asn188Thr]). BICD2 is a golgin and motor-adaptor protein involved in Golgi dynamics and vesicular and mRNA transport. Transient transfection of HeLa cells with all three mutant BICD2 cDNAs caused massive Golgi fragmentation. This observation was even more prominent in primary fibroblasts from an individual harboring c.2108C>T (p.Thr703Met) (affecting the C-terminal coiled-coil domain) and slightly less evident in individuals with c.563A>C (p.Asn188Thr) (affecting the N-terminal coiled-coil domain). Furthermore, BICD2 levels were reduced in affected individuals and trapped within the fragmented Golgi. Previous studies have shown that Drosophila mutant BicD causes reduced larvae locomotion by impaired clathrin-mediated synaptic endocytosis in neuromuscular junctions. These data emphasize the relevance of BICD2 in synaptic-vesicle recycling and support the conclusion that BICD2 mutations cause congenital slowly progressive dominant SMA.
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PMID:Mutations in BICD2, which encodes a golgin and important motor adaptor, cause congenital autosomal-dominant spinal muscular atrophy. 2366 16

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.
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PMID:Adult-onset SMALED2 due to a novel BICD2 mutation presenting with asymmetrical lower limb involvement. 3073 93