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J Neurol Sci. 2015 Dec 15;359(1-2):250-5. doi: 10.1016/j.jns.2015.10.045. Epub 2015 Oct 30.

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

Author information

1
Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan. Electronic address: tkawarai@tokushima-u.ac.jp.
2
Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan. Electronic address: ninigii@gmail.com.
3
Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan. Electronic address: noa@tokushima-u.ac.jp.
4
Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan. Electronic address: okkey19840323@gmail.com.
5
Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan. Electronic address: amiyashiro818@tokushima-u.ac.jp.
6
Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan. Electronic address: naoko@tokushima-u.ac.jp.
7
Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan. Electronic address: miyazaki@tokushima-u.ac.jp.
8
Laboratorio di Neurogenetica, CERC-IRCCS Santa Lucia, Rome, Italy; Dipartimento di Medicina dei Sistemi, Università di Roma "Tor Vergata", Rome, Italy. Electronic address: a.orlacchio@hsantalucia.it.
9
Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan. Electronic address: yizumi@tokushima-u.ac.jp.
10
Itsuki Hospital, Tokushima 770-0852, Japan. Electronic address: ynishida@shirt.ocn.ne.jp.
11
Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan. Electronic address: rkaji@tokushima-u.ac.jp.

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.

KEYWORDS:

Aberrant transcript; Nonsense-mediated mRNA decay; SPG11; Spastic paraplegia; Splice site donor mutation; Whole-exome sequencing

PMID:
26671123
DOI:
10.1016/j.jns.2015.10.045
[Indexed for MEDLINE]

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