Molecular Defects in the Motor Adaptor BICD2 Cause Proximal Spinal Muscular Atrophy with Autosomal-Dominant Inheritance

Abstract

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.

DYNC1H1 mutations associated with neurological diseases compromise processivity of dynein–dynactin–cargo adaptor complexes

“…Studies in rodents have shown that this protein plays an important role in dynein-based cargo transport in neurons (32)(33)(34). Consistent with these findings, missense mutations in the human BICD2 gene are also associated with SMALED (35)(36)(37) and cortical malformations (38,39). The protein uses an N-terminal coiled-coil domain (BICD2N) to bind dynein and dynactin and a C-terminal coiled coil (BICD2C) to bind cargos (17).…”

Dominant spinal muscular atrophy due to BICD2: a novel mutation refines the phenotype

“…1 Recently, BICD2 has been identified to cause dominant SMA. [1][2][3] Here, we provide additional evidence that BICD2 is a cause of dominant SMA and report detailed clinical, electrophysiological and MRI data from a three-generation family with cosegregation of a novel BICD2 mutation. These findings extend current notions of BICD2, demonstrating that it can present with adult-onset combined proximal and distal lower extremity SMA.…”

Mutations in cytoplasmic dynein and its regulators cause malformations of cortical development and neurodegenerative diseases

“…These patients are characterized by non-progressive congenital or earlyonset lower-limb-predominant weakness, which often results in significant mobility impairment. Secondly, Peeters et al [68] found mutations in BICD2 in independent Bulgarian families with autosomal-dominant proximal SMA. First, Oates et al [67] reported several missense mutations in BICD2 in patients affected with DCSMA or DCSMA with upper motor neuron features, or HSP (hereditary spastic paraplegia).…”

“…Secondly, Peeters et al [68] found mutations in BICD2 in independent Bulgarian families with autosomal-dominant proximal SMA. Some experimental evidence exists: BICD2-R501P and BICD2-S107L mutants increase dynein-dynactin binding and the BICD2-Q774G mutant decreases Rab6 binding [67,68]. Thirdly, Neveling et al [69] described four BICD2 mutations in Dutch and Canadian families afflicted with autosomal-dominant SMA, with weakness and atrophy of proximal and distal muscles mainly of the legs.…”