SPG7 mutational screening in spastic paraplegia patients supports a dominant effect for some mutations and a pathogenic role for p.A510V

Abstract

Mutations in the SPG7 gene were initially reported in patients with autosomal recessive hereditary spastic paraplegia (HSP). Recent works suggested a dominant effect for some SPG7 mutations. To characterize the SPG7 mutational spectrum in a large cohort of Spanish HSP patients, we sequenced the whole SPG7 gene in a total of 285 Spastic Paraplegia patients. Large gene rearrangements were also ascertained in some patients. We found a total of 14 SPG7 mutations (12 new) in 14 patients; 2 were large deletions. All the mutation carriers had an adult onset age but only five (35%) had a complicated phenotype. We identified a single mutation in 13 patients. Familial analysis suggested a dominant inheritance for one (p.Leu78*) of these mutations. Carriers of the rare p.A510V variant were significantly more frequent in patients vs healthy controls (3% vs 1%), suggesting a pathogenic role for this SPG7 variant. We reported a high frequency of patients with only one SPG7 mutation, and a putative pathogenic role for the p.A510V variant.

SPG7 mutations explain a significant proportion of French Canadian spastic ataxia cases

“…It was also found to be the most common SPG7 variant in several other populations. 9,15,16,25 Whereas it was first thought to be a benign variant, its pathogenicity was later demonstrated 15,22 and its presence in our FC spastic ataxia cohort supports this claim. In addition, this variant was present at a frequency slightly above 1% in our in-house exome database.…”

“…This study, as well as more recent publications on SPG7 mutation carriers, supports that cerebellar ataxia is a very frequent feature. [5][6][7]9,15 When present in milder adult-onset cases with spasticity, it suggests this diagnosis if not associated with cognitive deficit or peripheral neuropathy. In fact, cerebellar features, including ataxia, are more pronounced than spasticity in our cohort.…”

“…This is significantly higher than public databases (1000 Genomes, EVS and ExAc), but is comparable to what has been reported in the literature for British, Spanish, Italian and German populations. 9,10,15,22 A threshold of one percent is frequently used for the filtering of recessive variants. However, 'not so rare' variants have been identified as causing recessive diseases and this should be taken into account when searching for disease variants altering protein function.…”

“…Increasingly, reports documented that cerebellar ataxia and cerebellar atrophy on magnetic resonance imaging (MRI) are the most frequent additional features in complex SPG7 cases. 6,7,9,12,15 In a study of a large Dutch cohort, cerebellar ataxia was found in 57% of cases and it was even the dominating clinical symptom in some of these patients. 6 In addition, a recent report suggests that SPG7 mutations are a frequent cause of adult-onset undiagnosed cerebellar ataxia in patients of British descent.…”

“…4 Since then, a significant number of causative mutations were found in several HSP cohorts from different populations. [5][6][7][8][9][10][11][12][13][14] SPG7 can be characterized by a pure or complex HSP phenotype. Increasingly, reports documented that cerebellar ataxia and cerebellar atrophy on magnetic resonance imaging (MRI) are the most frequent additional features in complex SPG7 cases.…”