Eight Novel Mutations in SPG4 in a Large Sample of Patients With Hereditary Spastic Paraplegia

Abstract

Background: Hereditary spastic paraplegia (HSP) is a group of genetically heterogeneous disorders characterized by progressive spasticity of the lower limbs. Mutations in the SPG4 gene, which encodes spastin protein, are responsible for up to 45% of autosomal dominant cases.Objective: To search for disease-causing mutations in a large series of Italian patients with HSP.Design: Samples of DNA were analyzed by direct sequencing of all exons in SPG4. Samples from a subset of patients were also analyzed by direct sequencing of all exons in SPG3A, SPG6, SPG10, and SPG13. Setting: Molecular testing facility in Italy. Patients: Sixty unrelated Italian patients with pure (n=50) and complicated (n = 10) HSP. Main Outcome Measures: Mutations in SPG4, SPG3A, SPG6, SPG10, and SPG13.Results: We identified 12 different mutations, 8 of which were novel, in 13 patients. No mutations of any of the other HSP genes tested were found in 15 patients with sporadic pure HSP who did not have mutations in the SPG4 gene. Conclusions:The overall rate of mutation in the SPG4 gene within our sample was 22%, rising to 26% when only patients with pure HSP were considered. The negative result obtained in 15 patients without mutations in SPG4 in whom 4 other genes were analyzed (SPG3A, SPG6, SPG10, and SPG13) indicate that these genes are not frequently mutated in sporadic pure HSP.

SPAST mutations in Australian patients with hereditary spastic paraplegia

“…Both had complicated HSP. Our findings are consistent with previous population studies that report that 12–18% of patients with sporadic HSP have mutations in the SPAST gene …”

SPAST mutations in Australian patients with hereditary spastic paraplegia

“…Both had complicated HSP. Our findings are consistent with previous population studies that report that 12–18% of patients with sporadic HSP have mutations in the SPAST gene …”

Mutation analysis of the SPG4 gene in Italian patients with pure and complicated forms of spastic paraplegia

“…The obtained results are in accordance with previous studies from different populations except for the mutational frequency of the sporadic cases [2][3][4]13,17]. In fact, in our patients the mutational rate is higher than the already reported observations, this discrepancy possible due to the molecular techniques we used.…”

Isoform‐specific increase of spastin stability by N‐terminal missense variants including intragenic modifiers of SPG4 hereditary spastic paraplegia

“…Variant 44L, on the other hand, accounted for 0.8% of control chromosomes corresponding to a population frequency of 1.6%. This is well within the range reported in earlier studies [20][21][22][23]. 44L was also the only of the three variants present in our DNAs from the HSP cohort.…”

SPAST mutations in Australian patients with hereditary spastic paraplegia

“…Both had complicated HSP. Our findings are consistent with previous population studies that report that 12–18% of patients with sporadic HSP have mutations in the SPAST gene …”

Mutation analysis of the SPG4 gene in Italian patients with pure and complicated forms of spastic paraplegia

“…The obtained results are in accordance with previous studies from different populations except for the mutational frequency of the sporadic cases [2][3][4]13,17]. In fact, in our patients the mutational rate is higher than the already reported observations, this discrepancy possible due to the molecular techniques we used.…”

Isoform‐specific increase of spastin stability by N‐terminal missense variants including intragenic modifiers of SPG4 hereditary spastic paraplegia

“…Variant 44L, on the other hand, accounted for 0.8% of control chromosomes corresponding to a population frequency of 1.6%. This is well within the range reported in earlier studies [20][21][22][23]. 44L was also the only of the three variants present in our DNAs from the HSP cohort.…”

SPAST mutations in Australian patients with hereditary spastic paraplegia

“…Both had complicated HSP. Our findings are consistent with previous population studies that report that 12–18% of patients with sporadic HSP have mutations in the SPAST gene …”

Mutation analysis of the SPG4 gene in Italian patients with pure and complicated forms of spastic paraplegia

“…The obtained results are in accordance with previous studies from different populations except for the mutational frequency of the sporadic cases [2][3][4]13,17]. In fact, in our patients the mutational rate is higher than the already reported observations, this discrepancy possible due to the molecular techniques we used.…”

Isoform‐specific increase of spastin stability by N‐terminal missense variants including intragenic modifiers of SPG4 hereditary spastic paraplegia

“…Variant 44L, on the other hand, accounted for 0.8% of control chromosomes corresponding to a population frequency of 1.6%. This is well within the range reported in earlier studies [20][21][22][23]. 44L was also the only of the three variants present in our DNAs from the HSP cohort.…”