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. 2020 Sep;267(9):2732-2743.
doi: 10.1007/s00415-020-09861-w. Epub 2020 May 23.

SPG7 mutations in amyotrophic lateral sclerosis: a genetic link to hereditary spastic paraplegia

Alma Osmanovic  1   2 , Maylin Widjaja  1   2 , Alisa Förster  1 , Julia Weder  3 , Mike P Wattjes  4 , Inken Lange  2 , Anastasia Sarikidi  2 , Bernd Auber  1 , Peter Raab  4 , Anne Christians  1 , Matthias Preller  3 , Susanne Petri  2 , Ruthild G Weber  5
Affiliations

SPG7 mutations in amyotrophic lateral sclerosis: a genetic link to hereditary spastic paraplegia

Alma Osmanovic et al. J Neurol. 2020 Sep.

Abstract

Amyotrophic lateral sclerosis (ALS) and hereditary spastic paraplegia (HSP) are motor neuron diseases sharing clinical, pathological, and genetic similarities. While biallelic SPG7 mutations are known to cause recessively inherited HSP, heterozygous SPG7 mutations have repeatedly been identified in HSP and recently also in ALS cases. However, the frequency and clinical impact of rare SPG7 variants have not been studied in a larger ALS cohort. Here, whole-exome (WES) or targeted SPG7 sequencing was done in a cohort of 214 European ALS patients. The consequences of a splice site variant were analyzed on the mRNA level. The resulting protein alterations were visualized in a crystal structure model. All patients were subjected to clinical, electrophysiological, and neuroradiological characterization. In 9 of 214 (4.2%) ALS cases, we identified five different rare heterozygous SPG7 variants, all of which were previously reported in patients with HSP or ALS. All detected SPG7 variants affect the AAA+ domain of the encoded mitochondrial metalloprotease paraplegin and impair its stability or function according to predictions from mRNA analysis or crystal structure modeling. ALS patients with SPG7 mutations more frequently presented with cerebellar symptoms, flail arm or leg syndrome compared to those without SPG7 mutations, and showed a partial clinical overlap with HSP. Brain MRI findings in SPG7 mutation carriers included cerebellar atrophy and patterns suggestive of frontotemporal dementia. Collectively, our findings suggest that SPG7 acts as a genetic risk factor for ALS. ALS patients carrying SPG7 mutations present with distinct features overlapping with HSP, particularly regarding cerebellar findings.

Keywords: Amyotrophic lateral sclerosis; Hereditary spastic paraplegia; Motor neuron disease; SPG7; Whole-exome sequencing.

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Conflict of interest statement

AO received honoraria from Biogen; MPW received honoraria from Bayer, Biogen, Biologix, Celgene, Genilac, Imcyse, IXICO, Medison, Merck-Serono, Novartis, Roche, Sanofi-Genzyme, Spinger Healthcare, and Teva; PR received honoraria from Biogen and IXICO; SP received honoraria from Biogen, Cytokinetics, Inc., Desitin Pharma, Novartis, Roche, and Teva. MW, AF, JW, IL, AS, BA, AC, MP, and RGW report no conflict of interest.

Figures

Fig. 1
Fig. 1
Five heterozygous SPG7 mutations were detected in nine patients of a European ALS cohort. a Electropherograms demonstrating four rare heterozygous SPG7 missense variants in DNA from whole blood of eight ALS patients (affected nucleotides are designated by an arrow). All variants were predicted to be deleterious by at least one of two prediction tools, i.e. SIFT according to Alamut Visual Version 2.11, Interactive Biosoftware, Rouen, France or PolyPhen-2. b Missense variants detected in SPG7 affect amino acids highly or very highly conserved in paraplegin orthologs from different species (data taken from Alamut Visual Version 2.11). c Mapping of the amino acid residues affected by the identified SPG7 missense variants on a structural model of the AAA+ domain of human paraplegin (gold) with its substrate adenosine diphosphate (ADP). Close-up views show the mutated residues as obtained after energy minimization using Macromodel of the Schrödinger Suite and the OPLS3 force field [15, 16]. Variant p.(G349S) is part of the P-loop and may affect nucleotide binding and hydrolysis. In contrast, p.(R486Q) and p.(A510V) may disturb the structure of the α-helical bundle and thereby oligomerization. p.(R400W) is located in the N-terminal P-loop domain and as part of the hexamer interface may interfere with formation of the supracomplex. Sensor 1 is shown in green, Sensor 2 in blue, and the P-loop (Walker A motif) in cyan. d The rare heterozygous SPG7 splice site variant c.1552 + 1G > T detected in ALS patient MD018 on genomic DNA, its effect on cDNA, and its predicted consequence on the protein level. Given are electropherograms of targeted SPG7 sequencing on genomic DNA and cDNA from whole blood of patient MD018. By cDNA sequencing, an aberrant SPG7 transcript lacking exon 11 was identified. The predicted consequence of the aberrant transcript on the protein level was visualized in a crystal structure model of the functional AAA+ domain of paraplegin composed of the P-loop domain and the α-helical bundle. The skipping of exon 11 is predicted to result in a frameshift, leading to a premature stop codon. This would result in an altered α-helical bundle as indicated by the red color and a truncated peptidase domain
Fig. 2
Fig. 2
HSP- or FTD-associated patterns on brain MR images of ALS patients carrying heterozygous SPG7 mutations. a Sagittal T2-weighted scan of patient VALS008 carrying the p.(R400W) variant demonstrates vermis atrophy (designated by an arrow). In addition, CC thinning was observed with a total CC area of 496 mm2. b, c Pronounced parietotemporal atrophy was detected in three of seven ALS patients carrying rare heterozygous SPG7 variants, whereby coronal T2-weighted images of patient VALS008 carrying the p.(R400W) variant (b), and patient VALS125 carrying the p.(R486Q) variant (c) are shown
Fig. 3
Fig. 3
Overview of rare heterozygous deleterious SPG7 variants reported in ALS or HSP. a Summary of rare [MAF < 1% in Europeans (non-Finnish) according to the ExAC database] SPG7 variants predicted to be deleterious by at least one of two prediction tools, i.e. SIFT or PolyPhen-2, identified in ALS and HSP cases in a heterozygous state in our study and previously. The schematic illustration depicts all 17 exons of the SPG7 gene, whereby the genomic region encoding the AAA+ domain is highlighted in gold. Variants identified in ALS patients from our cohort are given in red. Variants previously described in ALS patients [26, 27, 38] are shown in green, and variants previously reported in HSP patients [12, 19, 39, 40] are indicated in blue. Protein sequence variants are given according to the Human Genome Variation Society recommendation v15.11. The exon structure of the SPG7 gene (NM_003119.2) was based on Alamut Visual Version 2.8. b The majority of rare heterozygous deleterious SPG7 variants in ALS and HSP patients affect the  AAA+ domain that couples ATP hydrolysis to protein remodeling, i.e. 5/5 (100%) identified in ALS patients of our study, 4/5 (80%) previously described in ALS patients [26, 27, 38], and 10/12 (83%) previously detected in HSP cases [12, 19, 39, 40]. †—variants identified in our study. #—variants previously described. AAA+ domain ATPases associated with diverse cellular activities domain, ALS amyotrophic lateral sclerosis, HSP hereditary spastic paraplegia
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