Sequence variants in SPAST, SPG3A and HSPD1 in hereditary spastic paraplegia
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Sequence variants in SPAST, SPG3A and HSPD1 in hereditary spastic paraplegia. / Svenstrup, Kirsten; Bross, Peter; Koefoed, Pernille; Hjermind, Lena E; Eiberg, Hans; Born, A Peter; Vissing, John; Gyllenborg, Jesper; Nørremølle, Anne; Hasholt, Lis; Nielsen, Jørgen E; Svenstrup, Kirsten; Bross, Peter; Koefoed, Pernille; Hjermind, Lena E; Eiberg, Hans; Born, A Peter; Vissing, John; Gyllenborg, Jesper; Nørremølle, Anne; Hasholt, Lis; Nielsen, Jørgen E.
In: Journal of the Neurological Sciences, Vol. 284, No. 1-2, 2009, p. 90-5.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Sequence variants in SPAST, SPG3A and HSPD1 in hereditary spastic paraplegia
AU - Svenstrup, Kirsten
AU - Bross, Peter
AU - Koefoed, Pernille
AU - Hjermind, Lena E
AU - Eiberg, Hans
AU - Born, A Peter
AU - Vissing, John
AU - Gyllenborg, Jesper
AU - Nørremølle, Anne
AU - Hasholt, Lis
AU - Nielsen, Jørgen E
AU - Svenstrup, Kirsten
AU - Bross, Peter
AU - Koefoed, Pernille
AU - Hjermind, Lena E
AU - Eiberg, Hans
AU - Born, A Peter
AU - Vissing, John
AU - Gyllenborg, Jesper
AU - Nørremølle, Anne
AU - Hasholt, Lis
AU - Nielsen, Jørgen E
N1 - 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
PY - 2009
Y1 - 2009
N2 - 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.
AB - 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.
U2 - 10.1016/j.jns.2009.04.024
DO - 10.1016/j.jns.2009.04.024
M3 - Journal article
C2 - 19423133
VL - 284
SP - 90
EP - 95
JO - Journal of the Neurological Sciences
JF - Journal of the Neurological Sciences
SN - 0022-510X
IS - 1-2
ER -
ID: 13012657