Kirsten Svenstrup, Peter Bross, Pernille Koefoed, Lena E Hjermind, Hans Eiberg, A Peter Born, John Vissing, Jesper Gyllenborg, Anne Nørremølle, Lis Hasholt, Jørgen E Nielsen, Kirsten Svenstrup, Peter Bross, Pernille Koefoed, Lena E Hjermind, Hans Eiberg, A Peter Born, John Vissing, Jesper Gyllenborg, Anne Nørremølle & 2 more
Hereditary spastic paraplegia (HSP) is a group of clinically and genetically heterogeneous neurodegenerative disorders characterized by progressive spasticity and weakness in the lower limbs. The most common forms of autosomal dominant HSP, SPG4 and SPG3, are caused by sequence variants in the SPAST and SPG3A genes, respectively. The pathogenic variants are scattered all over these genes and many variants are unique to a specific family. The phenotype in SPG4 patients can be modified by a variant in SPAST (p.Ser44Leu) and recently, a variant in HSPD1, the gene underlying SPG13, was reported as a second genetic modifier in SPG4 patients. In this study HSP patients were screened for variants in SPG3A, SPAST and HSPD1 in order to identify disease causing variations. SPAST was sequenced in all patients whereas subsets were sequenced in HSPD1 and in selected exons of SPG3A. SPG4 patients and their HSP relatives were genotyped for the modifying variant in HSPD1. We report six new sequence variants in SPAST including a fourth non synonymous sequence variant in exon 1 and two synonymous changes of which one has been found in a HSP patient previously, but never in controls. Of the novel variants in SPAST four were interpreted as disease causing. In addition one new disease causing sequence variant and one non pathogenic non synonymous variant were found in SPG3A. In HSPD1 we identified a sporadic patient homozygote for the potential modifying variation. The effect of the modifying HSPD1 variation was not supported by identification in one SPG4 family.
Keywords: Adenosine Triphosphatases; Amino Acid Motifs; Amino Acid Substitution; Cells, Cultured; Chaperonin 60; DNA Mutational Analysis; Denmark; Female; Fibroblasts; GTP Phosphohydrolases; Genetic Heterogeneity; Genetic Variation; Genotype; Humans; Male; Pedigree; Phenotype; Polymorphism, Single Nucleotide; RNA Splice Sites; Sequence Analysis, DNA; Sequence Deletion; Spastic Paraplegia, Hereditary