IRCCS Stella Maris, via dei Giacinti 2, 56028 Pisa, Italy.
BMC Med Genet. 2014 Apr 1;15:39. doi: 10.1186/1471-2350-15-39.
The hereditary spastic paraplegias (HSPs) are pleiomorphic disorders of motor pathway and a large number of affected genes have been discovered. Yet, mutations in SPG4/SPAST represent the most frequent molecular etiology in autosomal dominant (AD) patients and sporadic cases. We describe a large, AD-HSP Sardinian family where 5 out of several living members harbored a novel deletion affecting also the 5'UTR of SPAST and resulting in reduced expression of DPY30, the gene located upstream SPAST in a head-to-head manner.
A 54-year-old woman manifested leg stiffness at age 39 and required a cane to walk at age 50. Neurological examination disclosed mild spasticity and weakness in the legs, hyperreflexia in all limbs, and bilateral Babinski sign. She also complained of urinary urgency, but no additional neurological symptoms or signs were detected at examination. The clinical examination of 24 additional relatives disclosed three further affected individuals, two men and one woman. In the four symptomatic patients the initial manifestations were walking abnormalities and leg stiffness with a mean age at onset (SD) of 46.75 (5.44) years (range 39-51). The mean disease duration was 13.2 (13.4) years (range 6-35), and it correlated well with clinical severity (SPRS score) (r = 0.975, p = 0.005). One patient was confined to bed and displayed knee and ankle contractures, another case needed a cane to walk, and two individuals were able to walk without aids. Interestingly, a patient had also had a miscarriage during her first pregnancy.Gene testing revealed an heterozygous deletion spanning from the 5'-UTR to intron 4 of SPAST in the affected individuals and in one clinically unaffected woman. In three affected patients, the deletion also determined low mRNA levels of SPAST and DPY30, a component of the Set1-like multiprotein histone methyltransferase complex located upstream, head-to-head with SPAST.
Together with data described in a Japanese family, our findings seem to suggest that genes close to spastin might be candidates in modulating the clinical phenotype. This report endorses future research on the role of neighboring genes as potential players in SPG4 disease variability.
遗传性痉挛性截瘫（HSP）是一种运动通路的多态性疾病，已经发现了大量受影响的基因。然而，SPG4/SPAST 的突变代表了常染色体显性（AD）患者和散发性病例中最常见的分子病因。我们描述了一个大型的 AD-HSP 撒丁岛家族，其中 5 名在世的成员之一携带了一种新的缺失，该缺失还影响了 SPAST 的 5'UTR，导致位于 SPAST 上游的 DPY30 基因表达降低，这种方式呈头对头排列。
一名 54 岁女性在 39 岁时出现腿部僵硬，在 50 岁时需要使用拐杖行走。神经系统检查显示腿部轻度痉挛和无力，四肢反射亢进，双侧巴氏征阳性。她还抱怨尿急，但在检查中未发现其他神经系统症状或体征。对 24 名其他亲属的临床检查发现了另外 3 名受影响的个体，2 名男性和 1 名女性。在 4 名有症状的患者中，最初的表现是行走异常和腿部僵硬，发病年龄（标准差）为 46.75（5.44）岁（范围 39-51）。平均疾病持续时间为 13.2（13.4）年（范围 6-35），与临床严重程度（SPRS 评分）相关性良好（r=0.975，p=0.005）。一名患者卧床不起，出现膝关节和踝关节挛缩，另一名患者需要拐杖行走，还有两名患者能够无辅助行走。有趣的是，一名患者在第一次怀孕时也流产了。基因检测显示，在受影响的个体和一位临床未受影响的女性中，存在从 SPAST 的 5'UTR 到内含子 4 的杂合缺失。在 3 名受影响的患者中，缺失还导致 SPAST 和 DPY30 的 mRNA 水平降低，DPY30 是位于 SPAST 上游的 Set1 样多蛋白组蛋白甲基转移酶复合物的一个组成部分，以头对头的方式排列。
与在一个日本家庭中描述的数据一起，我们的发现似乎表明，SPAStin 附近的基因可能是调节临床表型的候选基因。本报告支持未来对邻近基因作为 SPG4 疾病变异性潜在参与者的作用的研究。
