De Novo and Dominantly Inherited SPTAN1 Mutations Cause Spastic Paraplegia and Cerebellar Ataxia

Abstract

Background: Pathogenic variants in SPTAN1 have been linked to a remarkably broad phenotypical spectrum. Clinical presentations include epileptic syndromes, intellectual disability, and hereditary motor neuropathy.

Objectives: We investigated the role of SPTAN1 variants in rare neurological disorders such as ataxia and spastic paraplegia.

Methods: We screened 10,000 NGS datasets across two international consortia and one local database, indicative of the level of international collaboration currently required to identify genes causative for rare disease. We performed in silico modeling of the identified SPTAN1 variants.

Results: We describe 22 patients from 14 families with five novel SPTAN1 variants. Of six patients with cerebellar ataxia, four carry a de novo SPTAN1 variant and two show a sporadic inheritance. In this group, one variant (p.Lys2083del) is recurrent in four patients. Two patients have novel de novo missense mutations (p.Arg1098Cys, p.Arg1624Cys) associated with cerebellar ataxia, in one patient accompanied by intellectual disability and epilepsy. We furthermore report a recurrent missense mutation (p.Arg19Trp) in 15 patients with spastic paraplegia from seven families with a dominant inheritance pattern in four and a de novo origin in one case. One further patient carrying a de novo missense mutation (p.Gln2205Pro) has a complex spastic ataxic phenotype. Through protein modeling we show that mutated amino acids are located at crucial interlinking positions, interconnecting the three-helix bundle of a spectrin repeat.

Conclusions: We show that SPTAN1 is a relevant candidate gene for ataxia and spastic paraplegia. We suggest that for the mutations identified in this study, disruption of the interlinking of spectrin helices could be a key feature of the pathomechanism. © 2022 International Parkinson and Movement Disorder Society.

Keywords: ataxia; next-generation sequencing; rare diseases; spastic paraplegia; spectrin.

Figure 1:. Function, structure, and subcellular compositions of spectrin.

Left, the mesh-like structure formed in the somatodendritic area. Middle, the scaffolding role of the α-II/beta-IV spectrin complex. Right, Membrane Periodic Structure (MPS) with actin rings along the distal axon.

Figure 2:. Graphical representation of SPTAN1 mutations reported with conclusive Mendelian inheritance.

Green, mutations identified in this study. Orange, mutations identified in HSP patients. Blue, mutations identified in HMN patients. In purple, mutation causative of sensorimotor neuropathy and developmental disorder. In black, mutations associated with epilepsy, autism or intellectual disability.

Figure 3:. Pedigrees of families with SPTAN1 mutations.

Pedigrees of families showing the segregation of SPTAN1 variants (NM_001130438.2:c.6247_6249delAAG, p.Lys2083del in families A-D), (NM_001130438.2:c.55C>T, p.Arg19Trp in families E-K), (NM_001130438.2:c.3292C>T, p.Arg1098Cys in family L), (NM_001130438.2:c.4870C>T, p.Arg1624Cys in family M), (NM_001130438.2:c.6614A>C, p.Gln2205Pro in family N); Affected (black symbols) and unaffected individuals (white symbols). Mutation results are indicated as carrier (−/+) or non-carrier (−/−).

Figure 4:. Protein modelling of respective SPTAN1 variants.

Top left panel: overview of the tetramer structure of the spectrin complex. Below, a graphical depiction of the α-II-spectrin protein structure with indication of the mutation locations. Top right panel: indication of the wild type Lys2083 residue, located across from three negatively charged residues. Bottom panel: comparison of the predicted wild type (WT) and mutant (MT) structures for every respective variant, with an overview of the location of the variant above. Positively charged residues are colored dark blue, negatively charged residues red. A hydrogen bond is indicated with a dotted line.