Highlights
- •We conducted mutational analysis of the SPAST and/or ATL1 genes in 206 HSP patients.
- •We identified 34 SPAST pathogenic variants and 3 ATL1 pathogenic variants in 52 patients.
- •Our study suggests that other genes may be involved in HSP in the Korean population.
Abstract
Hereditary spastic paraplegia (HSP) is a genetically heterogeneous group of diseases
characterized by insidiously progressive lower-extremity weakness and spasticity.
Spastic paraplegia 4 (SPAST) is the most common type of uncomplicated autosomal dominant HSP (40% of such cases),
and spastic paraplegia 3A (ATL1) is the second most common. Here, we conducted mutational analysis of the SPAST and/or ATL1 genes in 206 unrelated patients with HSP. DNA sequencing and multiplex ligation-dependent
probe amplification was used to analyze SPAST or ATL1 pathogenic variants. To confirm splice-site pathogenic variants, mRNA transcripts
were analyzed by reverse transcription-polymerase chain reactions and sequencing.
Among the 52 patients with medical records and SPAST or ATL1 gene pathogenic variants or novel unclassified variants, 50 showed spasticity or
weakness in their lower extremities. We identified 16 known and 18 novel SPAST pathogenic variants and 2 known and a novel splicing pathogenic variants in ATL1. We also identified 4 unclassified SPAST variants in 5 patients and an unclassified ATL1 variant in 1 patient. Further, a novel leaky-splicing variant (c.1537-11A>G) was
found in SPAST, which caused skipping of exon 13 or exons 13–14. Among the 206 unrelated patients
with HSP, SPAST or ATL1 pathogenic variants and potentially pathogenic variants were identified in 52 patients,
a low pathogenic variant rate compared to previous results. Results from our study
suggest that other genes may be involved in HSP in the Korean population.
Keywords
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References
- Spectrum of SPG4 mutations in autosomal dominant spastic paraplegia.Hum. Mol. Genet. 2000; 9: 637-644
- Hereditary spastic paraplegia: advances in genetic research. Hereditary Spastic Paraplegia Working group.Neurology. 1996; 46: 1507-1514
- Mutational spectrum of the SPG4 (SPAST) and SPG3A (ATL1) genes in Spanish patients with hereditary spastic paraplegia.BMC Neurol. 2010; 10: 89
- Hereditary spastic paraparesis: a review of new developments.J. Neurol. Neurosurg. Psychiatry. 2000; 69: 150-160
- Hereditary spastic paraplegia: clinical–genetic characteristics and evolving molecular mechanisms.Exp. Neurol. 2014; 261: 518-539
- Autosomal dominant spastic paraplegias: a review of 89 families resulting from a Portuguese survey.JAMA Neurol. 2013; 70: 481-487
- Expansion of mutation spectrum, determination of mutation cluster regions and predictive structural classification of SPAST mutations in hereditary spastic paraplegia.Eur. J. Hum. Genet. 2009; 17: 187-194
- Hereditary spastic paraparesis: disrupted intracellular transport associated with spastin mutation.Ann. Neurol. 2003; 54: 748-759
- Hereditary spastic paraplegia: clinical genetic study of 15 families.Arch. Neurol. 2004; 61: 849-855
- Spastin and microtubules: functions in health and disease.J. Neurosci. Res. 2007; 85: 2778-2782
- The nucleotide cycle of spastin correlates with its microtubule-binding properties.FEBS J. 2013; 280: 3868-3877
- Mutation analysis of SPG4 and SPG3A genes and its implication in molecular diagnosis of Korean patients with hereditary spastic paraplegia.Arch. Neurol. 2005; 62: 1118-1121
- MutationTaster evaluates disease-causing potential of sequence alterations.Nat. Methods. 2010; 7: 575-576
- Human non-synonymous SNPs: server and survey.Nucleic Acids Res. 2002; 30: 3894-3900
- Computational approaches for predicting the biological effect of p53 missense mutations: a comparison of three sequence analysis based methods.Nucleic Acids Res. 2006; 34: 1317-1325
- Predicting deleterious amino acid substitutions.Genome Res. 2001; 11: 863-874
- Detecting polymorphisms and mutations in candidate genes.Am. J. Hum. Genet. 2002; 71: 1251-1252
- Detection of novel mutations and review of published data suggests that hereditary spastic paraplegia caused by spastin (SPAST) mutations is found more often in males.J. Neurol. Sci. 2011; 306: 62-65
- Identification and expression analysis of spastin gene mutations in hereditary spastic paraplegia.Am. J. Hum. Genet. 2001; 68: 1077-1085
- High frequency of partial SPAST deletions in autosomal dominant hereditary spastic paraplegia.Neurology. 2006; 67: 1926-1930
- Hereditary spastic paraplegia due to SPAST mutations in 151 Dutch patients: new clinical aspects and 27 novel mutations.J. Neurol. Neurosurg. Psychiatry. 2010; 81: 1073-1078
- High frequency of partial SPAST deletions in autosomal dominant hereditary spastic paraplegia.Neurology. 2006; 67: 1926-1930
- Alu repeats and human genomic diversity.Nat. Rev. Genet. 2002; 3: 370-379
- Alu-specific microhomology-mediated deletion of the final exon of SPAST in three unrelated subjects with hereditary spastic paraplegia.Genet. Med. 2011; 13: 582-592
- A second leaky splice-site mutation in the spastin gene.Am. J. Hum. Genet. 2001; 69: 1407-1409
- Compound heterozygosity in the SPG4 gene causes hereditary spastic paraplegia.Clin. Genet. 2008; 73: 268-272
Article info
Publication history
Published online: July 16, 2015
Accepted:
July 15,
2015
Received in revised form:
July 14,
2015
Received:
April 22,
2015
Identification
Copyright
© 2015 Elsevier B.V. Published by Elsevier Inc. All rights reserved.
