ISPD gene mutations are a common cause of congenital and limb-girdle muscular dystrophies.
ISPD gene mutations are a common cause of congenital and limb-girdle muscular dystrophies.
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DOI：
10.1093/brain/aws312
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发表时间：
2013-01
期刊：
影响因子：
--
通讯作者：
Muntoni F
中科院分区：
文献类型：
--
作者：
Cirak S;Foley AR;Herrmann R;Willer T;Yau S;Stevens E;Torelli S;Brodd L;Kamynina A;Vondracek P;Roper H;Longman C;Korinthenberg R;Marrosu G;Nürnberg P;UK10K Consortium;Michele DE;Plagnol V;Hurles M;Moore SA;Sewry CA;Campbell KP;Voit T;Muntoni F
肌营养不良聚糖病是一组临床和遗传多样的复发性遗传性疾病，从最严重的先天性肌营养不良症，沃克-沃伯格综合征，到轻度形式的成人发作肢带型肌营养不良症。其标志是α-肌营养不良蛋白聚糖的功能性糖基化减少，这可以在肌肉活检中检测到。这种糖基化的一个重要部分是独特的O-甘露糖基化，对于α-肌营养不良聚糖与细胞外基质蛋白（如层粘连蛋白-α2）的相互作用至关重要。编码糖基化途径中蛋白质的八个基因的突变是导致约50%的肌营养不良症病例的原因。尽管使用传统的定位克隆进行了多次努力，但未解决的营养不良聚糖病病例的致病基因已经被发现了几年。在最近的一项合作研究中，我们发现一种新基因（称为类异戊二烯合成酶结构域（ISPD））的功能丧失隐性突变是沃克-沃伯格综合征的一个相对常见的原因。在这篇文章中，我们报告的ISPD基因参与轻度dystroglycanopathy表型，从先天性肌营养不良症肢带型肌营养不良症，并确定等位基因ISPD变异体在9例属于7个家庭。在两个流动的情况下，有证据表明，结构性脑参与，而在7个，临床表现仅限于营养不良的骨骼肌表型。虽然ISPD在哺乳动物中的功能尚不清楚，但该基因的突变明显导致α-肌营养不良聚糖的功能性糖基化减少，这不仅导致严重的Walker-Warburg综合征，也是轻度肌营养不良聚糖病的常见原因。
Dystroglycanopathies are a clinically and genetically diverse group of recessively inherited conditions ranging from the most severe of the congenital muscular dystrophies, Walker–Warburg syndrome, to mild forms of adult-onset limb-girdle muscular dystrophy. Their hallmark is a reduction in the functional glycosylation of α-dystroglycan, which can be detected in muscle biopsies. An important part of this glycosylation is a unique O-mannosylation, essential for the interaction of α-dystroglycan with extracellular matrix proteins such as laminin-α2. Mutations in eight genes coding for proteins in the glycosylation pathway are responsible for ∼50% of dystroglycanopathy cases. Despite multiple efforts using traditional positional cloning, the causative genes for unsolved dystroglycanopathy cases have escaped discovery for several years. In a recent collaborative study, we discovered that loss-of-function recessive mutations in a novel gene, called isoprenoid synthase domain containing (ISPD), are a relatively common cause of Walker–Warburg syndrome. In this article, we report the involvement of the ISPD gene in milder dystroglycanopathy phenotypes ranging from congenital muscular dystrophy to limb-girdle muscular dystrophy and identified allelic ISPD variants in nine cases belonging to seven families. In two ambulant cases, there was evidence of structural brain involvement, whereas in seven, the clinical manifestation was restricted to a dystrophic skeletal muscle phenotype. Although the function of ISPD in mammals is not yet known, mutations in this gene clearly lead to a reduction in the functional glycosylation of α-dystroglycan, which not only causes the severe Walker–Warburg syndrome but is also a common cause of the milder forms of dystroglycanopathy.
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影响因子：
6.4
作者：
Jimenez-Mallebrera, Cecilia;Torelli, Silvia;Muntoni, Francesco
通讯作者：
Muntoni, Francesco
使用下一代 DNA 测序数据进行变异发现和基因分型的框架。
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
4.5
作者：
Lefeber DJ;de Brouwer AP;Morava E;Riemersma M;Schuurs-Hoeijmakers JH;Absmanner B;Verrijp K;van den Akker WM;Huijben K;Steenbergen G;van Reeuwijk J;Jozwiak A;Zucker N;Lorber A;Lammens M;Knopf C;van Bokhoven H;Grünewald S;Lehle L;Kapusta L;Mandel H;Wevers RA
通讯作者：
Wevers RA
影响因子：
3.5
作者：
Brockington, M;Yuva, Y;Muntoni, F
通讯作者：
Muntoni, F
影响因子：
9.8
作者：
Brockington, M;Blake, DJ;Muntoni, F
通讯作者：
Muntoni, F