Spinal Muscular Atrophy with Pontocerebellar Hypoplasia Is Caused by a Mutation in the VRK1 Gene
Spinal Muscular Atrophy with Pontocerebellar Hypoplasia Is Caused by a Mutation in the VRK1 Gene
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DOI：
10.1016/j.ajhg.2009.07.006
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发表时间：
2009-08-14
影响因子：
9.8
通讯作者：
Levy-Lahad, Ephrat
中科院分区：
文献类型：
--
作者：
Renbaum, Paul;Kellerman, Efrat;Levy-Lahad, Ephrat
脊髓性肌萎缩症（sma）是一种遗传和临床异质性的疾病，其特征是脊髓前角细胞的退化和丧失，导致肌肉无力和萎缩。脊髓性肌萎缩伴桥小脑发育不全（SMA- pch，又称桥小脑发育不全1型[PCH1]）是一种罕见的婴儿SMA变异，具有其他临床表现，其遗传基础尚不清楚。我们使用纯合子作图和定位克隆方法在一个德系犹太血统的近亲家庭中发现了牛痘相关激酶1基因（VRK1）的无义突变是SMA-PCH的原因。VRK1是哺乳动物VRK家族的三个成员之一，是一种丝氨酸/苏氨酸激酶，可磷酸化p53和CREB，对核膜的形成至关重要。其作为SMA-PCH相关基因的鉴定表明VRK蛋白在神经元发育和维持中的新作用，并提示VRK基因是相关表型的候选基因。
The spinal muscular atrophies (SMAs) are a genetically and clinically heterogeneous group of disorders characterized by degeneration and loss of anterior horn cells in the spinal cord, leading to muscle weakness and atrophy. Spinal muscular atrophy with pontocerebellar hypoplasia (SMA-PCH, also known as pontocerebellar hypoplasia type 1 [PCH1]) is one of the rare infantile SMA variants that include additional clinical manifestations, and its genetic basis is unknown. We used a homozygosity mapping and positional cloning approach in a consanguineous family of Ashkenazi Jewish origin and identified a nonsense mutation in the vaccinia-related kinase 1 gene (VRK1) as a cause of SMA-PCH. VRK1, one of three members of the mammalian VRK family, is a serine/threonme kinase that phosphorylates p53 and CREB and is essential for nuclear envelope formation. Its identification as a gene involved in SMA-PCH implies new roles for the VRK proteins in neuronal development and maintenance and suggests the VRK genes as candidates for related phenotypes.