Large deletion involving the 5'-UTR in the spastin gene caused mild phenotype of autosomal dominant hereditary spastic paraplegia
Large deletion involving the 5'-UTR in the spastin gene caused mild phenotype of autosomal dominant hereditary spastic paraplegia
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DOI：
10.1002/ajmg.a.30510
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发表时间：
2005-02-15
影响因子：
2
通讯作者：
Eguchi, K
中科院分区：
文献类型：
--
作者：
Iwanaga, H;Tsujino, A;Eguchi, K
由于位于2 p22-p21的spastin基因（SPG 4）突变引起的遗传性痉挛性截瘫（HSP）是常染色体显性（AD）HSP的最常见形式。我们进行了基于PCR的SPG 4直接测序，随后进行了连锁分析和随后的Southern印迹分析，在大型日本家族中，33名成员中有20名进行了神经学评估，因此6名受到HSP的影响。临床评价显示，患者的平均发病年龄较大，残疾程度低于先前报道的典型SPG 4突变患者。基因组DNA和RT-PCR产物的直接测序没有显示SPG 4突变，尽管在2 p处与SPG 4位点有很强的连锁。Southern印迹分析表明SPG 4的5 '-UTR缺失。进一步的序列分析证实了SPG 4的从5 '-UTR到内含子1的2307-bp的杂合缺失。结果表明，突变的等位基因的转录从一个真实的起始位点开始，但缺乏一个真实的翻译起始位点的外显子1，因为缺乏剪接供体位点和编码区。这些异常的转录本可能导致RNA快速降解。我们发现的新的难治性突变扩大了SPG 4突变的范围。这些发现表明SPG 4的结构基因组异常比预期的更频繁，这解释了先前报道的病例更可行，其中SPG 4突变未能被识别，但该疾病与2 p有关。(C)2005 Wiley-Liss，Inc.
Hereditary spastic paraplegia (HSP) due to mutations in the spastin gene (SPG4) located to 2p22-p21 is the most common form of autosomal dominant (AD) HSP. We performed PCR-based direct sequencing of SPG4, followed by a linkage analysis and subsequent Southern blot analysis in large Japanese kindred where 20 of 33 members were evaluated neurologically, and consequently 6 were affected with HSP. Clinical evaluation showed that the mean age at disease onset of the patients was older and the disability was less severe than those of previously reported typical patients with SPG4 mutations. Direct sequencing of genomic DNA and RT-PCR product did not show a SPG4 mutation despite of a strong linkage to the SPG4 locus at 2p. Southern blot analysis suggested a deletion involving the 5'-UTR of SPG4. Further sequence analysis confirmed a heterozygous 2307-bp deletion spanning from the 5'-UTR to intron 1 of SPG4. The results suggested that transcription of the mutated allele starts from an authentic initiation site, but lacks an authentic translational start site of exon 1 because of a deficient splice donor site and coding region. The abnormal transcripts may result in rapid RNA decay. The novel refractory mutation we identified widens the spectrum of SPG4 mutations. These findings suggest that structural genomic abnormalities of SPG4 are more frequent than expected, and this explains previously reported cases more feasibly in which SPG4 mutations were failed to be identified but the disease was linked to 2p. (C) 2005 Wiley-Liss, Inc.