title: Dominant spinal muscular atrophy is caused by mutations in BICD2, an important golgin protein.
abstract: 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.
authors.affiliation: Institute of Human Genetics, Institute for Genetics and Center for Molecular Medicine of The University of Cologne Cologne, Germany.
authors.forename: Lilian A
authors.initials: LA
authors.lastname: Martinez-Carrera
authors.affiliation: Institute of Human Genetics, Institute for Genetics and Center for Molecular Medicine of The University of Cologne Cologne, Germany.
authors.forename: Brunhilde
authors.initials: B
authors.lastname: Wirth
keywords: BICD2; Golgi fragmentation; RAB6A; SMA; SMALED2; dynactin; dynein; endocytosis