Spastic paraplegia type 4: A novel SPAST splice site donor mutation and expansion of the phenotype variability

被引：15

作者：

Kawarai, Toshitaka ^{[1
]}

Montecchiani, Celeste ^{[2
,3
]}

Miyamoto, Ryosuke ^{[1
]}

Gaudiello, Fabrizio ^{[2
]}

Caltagirone, Carlo ^{[4
,5
]}

Izumi, Yuishin ^{[1
]}

Kaji, Ryuji ^{[1
]}

Orlacchio, Antonio ^{[2
,3
]}

机构：

[1] Tokushima Univ, Inst Biomed Sci, Dept Clin Neurosci, Grad Sch, 3-18-15 Kuramoto Cho, Tokushima 7700042, Japan

[2] Ist Ricovero & Cura Carattere Sci IRCCS Santa Luc, CERC, Lab Neurogenet, 64 Via Fosso di Fiorano, I-00143 Rome, Italy

[3] Univ Perugia, Dipartimento Sci Chirurg & Biomed, Perugia, Italy

[4] IRCCS Santa Lucia, Lab Neurol Clin & Comportamentale, Rome, Italy

[5] Univ Roma Tor Vergata, Dipartimento Med Sistemi, Rome, Italy

来源：

JOURNAL OF THE NEUROLOGICAL SCIENCES | 2017年 / 380卷

基金：

日本学术振兴会;

关键词：

Spastic paraplegia type 4 (SPG4); SPAST; Splice site donor variant; Nonsense-Mediated mRNA Decay (NMD); Phenotype variability; MESSENGER-RNA; SEQUENCE; DISEASE; FREQUENT; ATAXIA; LOCUS; SPG4; MAPS; PCR;

D O I：

10.1016/j.jns.2017.07.011

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

Mutations in SPG4/SPAST are the most frequent molecular aetiology in the autosomal dominant form of hereditary spastic paraplegia (HSP). Loss-of-function and haploinsufficiency in SPAST have been demonstrated and the pure form of spastic paraplegia is a main clinical manifestation. This study is to explore the novel SPAST splice site donor variant, c.1004 + 3A> C, in seven patients from two families, one from Italy and the other from Japan. Exon 6 is skipped out by the variant, leading to a premature termination of translation, p.Gly290Trpfs*S. Measurement of SPAS7 transcripts in lymphocytes demonstrated a reduction through nonsense-mediated mRNA decay (NMD). Intra- and inter-familial phenotypic variations were observed, including age-at-onset, severity of spasticity, and scoliosis. Our study demonstrated further evidence of allelic heterogeneity in SPG4, dosage effects through NMD, and broad clinical features of the SPAST mutation. (C) 2017 Elsevier B.V. All rights reserved.

引用

页码：92 / 97

页数：6

共 24 条

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