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

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.

The Novel Regulatory Role of lncRNA-miRNA-mRNA Axis in Amyotrophic Lateral Sclerosis: An Integrated Bioinformatics Analysis

“…Familial ALS accounts for only 5%-10% of ALS cases, while sporadic ALS accounts for 90%-95% of cases [ 11 ]. Regardless of whether there is a family history, the disease pathogenesis is related to mutations in genes including SOD1 [ 7 , 12 ], OPTN [ 6 , 13 ], UBQLN2 [ 11 ], C9orf72 [ 8 ], SQSTM1 [ 2 ], SETX [ 2 ], GARP [ 9 ], PFN1 [ 14 ], and SPG7 [ 15 ] and genes that encode RNA-binding proteins [ 16 ], such as TARDBP , hnRNPA2B1 , hnRNPA1 , and FUS .…”

Evidence for Non‐Mendelian Inheritance in Spastic Paraplegia 7

“…Spastic paraplegia 7 (SPG7) is the first‐identified autosomal recessive (AR) type of HSP, accounting for 5%–12% of AR‐HSP 4 . Pathogenic variants in SPG7 may also lead to spastic and/or cerebellar ataxia, peripheral neuropathy with no other neurological symptoms, primary progressive multiple sclerosis, amyotrophic lateral sclerosis, primary lateral sclerosis, parkinsonism, limb dystonia, and isolated dominant optic atrophy 5‐13 . Although the inheritance of SPG7 is considered to be AR, several reports suggested that SPG7 variants may also cause autosomal dominant (AD) HSP 5,14‐16 .…”

“…4 Pathogenic variants in SPG7 may also lead to spastic and/or cerebellar ataxia, peripheral neuropathy with no other neurological symptoms, primary progressive multiple sclerosis, amyotrophic lateral sclerosis, primary lateral sclerosis, parkinsonism, limb dystonia, and isolated dominant optic atrophy. [5][6][7][8][9][10][11][12][13] Although the inheritance of SPG7 is considered to be AR, several reports suggested that SPG7 variants may also cause autosomal dominant (AD) HSP. 5,[14][15][16] None of these studies examined the possibility of digenic inheritance (carrying two mutations in different HSP genes), therefore the role of SPG7 in AD-HSP remains controversial.…”

Heterozygous DHTKD1 Variants in Two European Cohorts of Amyotrophic Lateral Sclerosis Patients

“…Additionally, certain genetic aberrations have been reported to modify the ALS phenotype, suggesting that genetic factors also shape the clinical presentation of ALS [ 4 ]. Moreover, some of the genes identified in ALS patients are also causative for other neurodegenerative disorders, such as C9orf72 and TARDBP for frontotemporal dementia (FTD) and Parkinson’s disease, and SPG7 and SPG11 for hereditary spastic paraplegia, indicating shared pathomechanisms [ 4 , 5 , 6 , 7 ]. In fact, it appears as though most, if not all ALS genes may be pleiotropic [ 8 ].…”