Mutation screening of spastin, atlastin, and REEP1 in hereditary spastic paraplegia

Abstract

Hereditary spastic paraplegia (HSP) comprises a group of clinically and genetically heterogeneous diseases that affect the upper motor neurons and their axonal projections. Over 40 chromosomal loci have been identified for autosomal dominant, recessive, and X-linked HSP. Mutations in the genes atlastin, spastin and REEP1 are estimated to account for up to 50% of autosomal-dominant HSP and currently guide the molecular diagnosis of HSP. Here, we report the mutation screening results of 120 HSP patients from North America for spastin, atlastin, and REEP1, with the latter one partially reported previously. We identified mutations in 36.7% of all tested HSP patients and describe 20 novel changes in spastin and atlastin. Our results add to a growing number of HSP disease-associated variants and confirm the high prevalence of atlastin, spastin, and REEP1 mutations in the HSP patient population.

Figure 1

Schematic of conserved domains of spastin (SPAST) and atlastin (ATL1) showing that the majority of mutations cluster in the AAA domain and the GBP/Ras-like GTPase domain respectively. Novel mutations are shown in boldface, coding changes are listed above the protein depiction and splicing mutations are listed below. TM = transmembrane domain; MIT = Microtubule Interacting and Trafficking molecule domain; MTBD = Microtubule-Binding Domain; AAA = ATPases Associated with a wide variety of Activities.