title: Late-onset spastic paraplegia: Aberrant SPG11 transcripts generated by a novel splice site donor mutation.
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.
authors.affiliation: Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan. Electronic address: tkawarai@tokushima-u.ac.jp.
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Kawarai
authors.affiliation: Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan. Electronic address: ninigii@gmail.com.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Miyamoto
authors.affiliation: Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan. Electronic address: noa@tokushima-u.ac.jp.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Mori
authors.affiliation: Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan. Electronic address: okkey19840323@gmail.com.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Oki
authors.affiliation: Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan. Electronic address: amiyashiro818@tokushima-u.ac.jp.
authors.forename: Ai
authors.initials: A
authors.lastname: Tsukamoto-Miyashiro
authors.affiliation: Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan. Electronic address: naoko@tokushima-u.ac.jp.
authors.forename: Naoko
authors.initials: N
authors.lastname: Matsui
authors.affiliation: Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan. Electronic address: miyazaki@tokushima-u.ac.jp.
authors.forename: Yoshimichi
authors.initials: Y
authors.lastname: Miyazaki
authors.affiliation: 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.
authors.forename: Antonio
authors.initials: A
authors.lastname: Orlacchio
authors.affiliation: Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan. Electronic address: yizumi@tokushima-u.ac.jp.
authors.forename: Yuishin
authors.initials: Y
authors.lastname: Izumi
authors.affiliation: Itsuki Hospital, Tokushima 770-0852, Japan. Electronic address: ynishida@shirt.ocn.ne.jp.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Nishida
authors.affiliation: Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan. Electronic address: rkaji@tokushima-u.ac.jp.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Kaji
mesh_terms: D000328:Adult; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D006801:Humans; D007438:Introns; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation / Q000235:genetics* / Q000276:immunology*; D010264:Paraplegia / Q000235:genetics*; D011506:Proteins / Q000235:genetics*
chemical_list: D011506:Proteins; C520412:SPG11 protein, human
keywords: Aberrant transcript; Nonsense-mediated mRNA decay; SPG11; Spastic paraplegia; Splice site donor mutation; Whole-exome sequencing