We identified a novel homozygous mutation in the splice site donor (SSD) of intron 30 (c.5866 + 1G > A) in consanguineous Japanese SPG11 siblings showing late-onset spastic paraplegia using the whole-exome sequencing. Phenotypic variability was observed, including age-at-onset, dysarthria and pes cavus. Coding DNA sequencing revealed that the mutation affected the recognition of the constitutive SSD of intron 30, splicing upstream onto a nearby cryptic SSD in exon 30. The use of constitutive splice sites of intron 29 was confirmed by sequencing. The mutant transcripts are mostly subject to degradation by the nonsense-mediated mRNA decay system. SPG11 transcripts, escaping from the nonsense-mediated mRNA decay pathway, would generate a truncated protein (p.Tyr1900Phefs5X) containing the first 1899 amino acids and followed by 4 aberrant amino acids. This study showed a successful clinical application of whole-exome sequencing in spastic paraplegia and demonstrated a further evidence of allelic heterogeneity in SPG11. The confirmation of aberrant transcript by splice site mutation is a prerequisite for a more precise molecular diagnosis.

Kawarai, T., Miyamoto, R., Mori, A., Oki, R., Tsukamoto-Miyashiro, A., Matsui, N., et al. (2015). Late-onset spastic paraplegia: Aberrant SPG11 transcripts generated by a novel splice site donor mutation. JOURNAL OF THE NEUROLOGICAL SCIENCES, 359(1-2), 250-255 [10.1016/j.jns.2015.10.045].

Late-onset spastic paraplegia: Aberrant SPG11 transcripts generated by a novel splice site donor mutation

ORLACCHIO, ANTONIO;
2015

Abstract

We identified a novel homozygous mutation in the splice site donor (SSD) of intron 30 (c.5866 + 1G > A) in consanguineous Japanese SPG11 siblings showing late-onset spastic paraplegia using the whole-exome sequencing. Phenotypic variability was observed, including age-at-onset, dysarthria and pes cavus. Coding DNA sequencing revealed that the mutation affected the recognition of the constitutive SSD of intron 30, splicing upstream onto a nearby cryptic SSD in exon 30. The use of constitutive splice sites of intron 29 was confirmed by sequencing. The mutant transcripts are mostly subject to degradation by the nonsense-mediated mRNA decay system. SPG11 transcripts, escaping from the nonsense-mediated mRNA decay pathway, would generate a truncated protein (p.Tyr1900Phefs5X) containing the first 1899 amino acids and followed by 4 aberrant amino acids. This study showed a successful clinical application of whole-exome sequencing in spastic paraplegia and demonstrated a further evidence of allelic heterogeneity in SPG11. The confirmation of aberrant transcript by splice site mutation is a prerequisite for a more precise molecular diagnosis.
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore MED/26 - Neurologia
eng
Con Impact Factor ISI
Aberrant transcript; Nonsense-mediated mRNA decay; Spastic paraplegia; SPG11; Splice site donor mutation; Whole-exome sequencing; Neurology (clinical); Neurology
www.elsevier.com/locate/jns
Kawarai, T., Miyamoto, R., Mori, A., Oki, R., Tsukamoto-Miyashiro, A., Matsui, N., et al. (2015). Late-onset spastic paraplegia: Aberrant SPG11 transcripts generated by a novel splice site donor mutation. JOURNAL OF THE NEUROLOGICAL SCIENCES, 359(1-2), 250-255 [10.1016/j.jns.2015.10.045].
Kawarai, T; Miyamoto, R; Mori, A; Oki, R; Tsukamoto Miyashiro, A; Matsui, N; Miyazaki, Y; Orlacchio, A; Izumi, Y; Nishida, Y; Kaji, R
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2108/159286
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