A novel insertion mutation in atlastin 1 is associated with spastic quadriplegia, increased membrane tethering, and aberrant conformational switching

Abstract

Hereditary spastic paraplegia (HSP) comprises a heterogeneous group of neuropathies affecting upper motor neurons and causing progressive gait disorder. Mutations in the gene SPG3A/atlastin-1 ( ATL1 ), encoding a dynamin superfamily member, which utilizes the energy from GTP hydrolysis for membrane tethering and fusion to promote the formation of a highly branched, smooth endoplasmic reticulum (ER), account for approximately 10% of all HSP cases. The continued discovery and characterization of novel disease mutations are crucial for our understanding of HSP pathogenesis and potential treatments. Here, we report a novel disease-causing, in-frame insertion in the ATL1 gene, leading to inclusion of an additional asparagine residue at position 417 (N417ins). This mutation correlates with complex, early-onset spastic quadriplegia affecting all four extremities, generalized dystonia, and a thinning of the corpus callosum. We show using limited proteolysis and FRET-based studies that this novel insertion affects a region in the protein central to intramolecular interactions and GTPase-driven conformational change, and that this insertion mutation is associated with an aberrant prehydrolysis state. While GTPase activity remains unaffected by the insertion, membrane tethering is increased, indicative of a gain-of-function disease mechanism uncommon for ATL1-associated pathologies. In conclusion, our results identify a novel insertion mutation with altered membrane tethering activity that is associated with spastic quadriplegia, potentially uncovering a broad spectrum of molecular mechanisms that may affect neuronal function.

High Atlastin 2-2 (ATL2-2) Expression Associates with Worse Prognosis in Estrogen-Receptor-Positive Breast Cancer

“…It occurs when ATL2 reshapes the ER, which redistributes the RyR2 calcium channel and calcium release, inducing IP 3 R calcium release [ 56 ]. In comparison to ATL1 in which mutations result in spastic paraplegia, which emphasizes the importance of a branched ER network in neuronal axons ([ 57 ] and references therein), ATL2 may be important in filipods and other mechanisms involved in cellular migration.…”

Clinical features and genetic spectrum of Chinese patients with hereditary spastic paraplegia: A 14-year study

“…Moreover, we identified an unreported variant in the SPG3A causative gene ALT1. SPG3A is the most common early-onset AD-HSP, presenting with slowly progressive p-HSP with an AAO usually less than 10 years, and is the second most frequently found in AD-HSP patients in China (Giordani et al, 2021;Kelly et al, 2022). The newly reported variant, c.1030C>A, is a missense mutation that may cause destructive effects on protein function according to prediction software.…”

Atlastin-1 regulates endosomal tubulation and lysosomal proteolysis in human cortical neurons

“…[27] It has generally been thought that most atlastin-1 mutations act via a dominant negative mechanism, although gain of function mutations have been associated with a more severe phenotype and the presence of the loss of function mutations described above suggests that at least in some cases a haploinsufficiency mechanism operates. [27, 28] In this regard, recent in vivo data derived from engineering human mutations into Drosophila atlastin did not support a dominant negative mechanism and the probability of loss intolerance (pLI) score for the ATL1 gene is 0.98, indicating that it is intolerant of haploinsufficiency. [29, 30] Furthermore, rare cases of HSP caused by autosomal recessive loss-of-function ATL1 mutations have been described.…”