Identification and expression analysis of spastin gene mutations in hereditary spastic paraplegia

I. K. Svenson, A. E. Ashley-Koch, P. C. Gaskell, T. J. Riney, W. J K Cumming, H. M. Kingston, E. L. Hogan, R. M N Boustany, Jeffery M Vance, M. A. Nance, Margaret A Pericak-Vance, D. A. Marchuk

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Abstract

Pure hereditary spastic paraplegia (SPG) type 4 is the most common form of autosomal dominant hereditary SPG, a neurodegenerative disease characterized primarily by hyperreflexia and progressive spasticity of the lower limbs. It is caused by mutations in the gene encoding spastin, a member of the AAA family of ATPases. We have screened the spastin gene for mutations in 15 families consistent with linkage to the spastin gene locus, SPG4, and have identified 11 mutations, 10 of which are novel. Five of the mutations identified are in noninvariant splice-junction sequences. Reverse transcription-PCR analysis of mRNA from patients shows that each of these five mutations results in aberrant splicing. One mutation was found to be "leaky," or partially penetrant; that is, the mutant allele produced both mutant (skipped exon) and wild-type (full-length) transcripts. This phenomenon was reproduced in in vitro splicing experiments, with a minigene splicing-vector construct only in the context of the endogenous splice junctions flanking the splice junctions of the skipped exon. In the absence of endogenous splice junctions, only mutant transcript was detected. The existence of at least one leaky mutation suggests that relatively small differences in the level of wild-type spastin expression can have significant functional consequences. This may account, at least in part, for the wide ranges in age at onset, symptom severity, and rate of symptom progression that have been reported to occur both among and within families with SPG linked to SPG4. In addition, these results suggest caution in the interpretation of data solely obtained with minigene constructs to study the effects of sequence variation on splicing. The lack of full genomic sequence context in these constructs can mask important functional consequences of the mutation.

Original languageEnglish
Pages (from-to)1077-1085
Number of pages9
JournalAmerican Journal of Human Genetics
Volume68
Issue number5
DOIs
StatePublished - May 21 2001
Externally publishedYes

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Hereditary Spastic Paraplegia
Mutation
Genes
Exons
Abnormal Reflexes
Paraplegia
Masks
Age of Onset
Neurodegenerative Diseases
Reverse Transcription
Adenosine Triphosphatases
Lower Extremity
Alleles
Polymerase Chain Reaction
Messenger RNA

ASJC Scopus subject areas

  • Genetics

Cite this

Svenson, I. K., Ashley-Koch, A. E., Gaskell, P. C., Riney, T. J., Cumming, W. J. K., Kingston, H. M., ... Marchuk, D. A. (2001). Identification and expression analysis of spastin gene mutations in hereditary spastic paraplegia. American Journal of Human Genetics, 68(5), 1077-1085. https://doi.org/10.1086/320111

Identification and expression analysis of spastin gene mutations in hereditary spastic paraplegia. / Svenson, I. K.; Ashley-Koch, A. E.; Gaskell, P. C.; Riney, T. J.; Cumming, W. J K; Kingston, H. M.; Hogan, E. L.; Boustany, R. M N; Vance, Jeffery M; Nance, M. A.; Pericak-Vance, Margaret A; Marchuk, D. A.

In: American Journal of Human Genetics, Vol. 68, No. 5, 21.05.2001, p. 1077-1085.

Research output: Contribution to journalArticle

Svenson, IK, Ashley-Koch, AE, Gaskell, PC, Riney, TJ, Cumming, WJK, Kingston, HM, Hogan, EL, Boustany, RMN, Vance, JM, Nance, MA, Pericak-Vance, MA & Marchuk, DA 2001, 'Identification and expression analysis of spastin gene mutations in hereditary spastic paraplegia', American Journal of Human Genetics, vol. 68, no. 5, pp. 1077-1085. https://doi.org/10.1086/320111
Svenson IK, Ashley-Koch AE, Gaskell PC, Riney TJ, Cumming WJK, Kingston HM et al. Identification and expression analysis of spastin gene mutations in hereditary spastic paraplegia. American Journal of Human Genetics. 2001 May 21;68(5):1077-1085. https://doi.org/10.1086/320111
Svenson, I. K. ; Ashley-Koch, A. E. ; Gaskell, P. C. ; Riney, T. J. ; Cumming, W. J K ; Kingston, H. M. ; Hogan, E. L. ; Boustany, R. M N ; Vance, Jeffery M ; Nance, M. A. ; Pericak-Vance, Margaret A ; Marchuk, D. A. / Identification and expression analysis of spastin gene mutations in hereditary spastic paraplegia. In: American Journal of Human Genetics. 2001 ; Vol. 68, No. 5. pp. 1077-1085.
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