Article

Spinal Muscular Atrophy with Pontocerebellar Hypoplasia Is Caused by a Mutation in the VRK1 Gene

Medical Genetics Institute, Shaare Zedek Medical Center, Jerusalem, Israel.
The American Journal of Human Genetics (Impact Factor: 10.93). 08/2009; 85(2):281-9. DOI: 10.1016/j.ajhg.2009.07.006
Source: PubMed

ABSTRACT

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/threonine 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.

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Available from: Ephrat Levy-Lahad, Sep 03, 2014
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    • "The first report of this condition by Norman, after whom the condition is named, described cerebellar hypoplasia in Werding-Hoffman disease, and he hypothesized that the association may be linked to a single genetic abnormality[2]. This has proven to be the case indeed, as cases of pontocerebellar hypoplasia with infantile spinal atrophy have been linked to homozygous mutations in the vaccinia-related kinase 1 (VRK1) gene[3]as well as TSEN54 and RARS2 genes[1]. Unlike previously reported cases, this child additionally presented with tonic seizures and a burst suppression EEG pattern that define Ottahara syndrome (Early Infantile Epileptic encephalopathy with burst-suppression)[4]. "

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    • "p53 regulates cell division and death during nervous system development and in response to neuronal insult or injury during life. Recessive mutations in Ataxia telangiectasia mutated (ATM), which phosphorylate p53 in response to DNA damage cause ataxia telangiectasia, in which loss of cerebellar neurons and ataxia are prominent features.[59] Moreover, p53 interacts directly with SMN1, an association disrupted by SMN1 mutations associated with SMA,[81] and might be of relevance to SMA pathogenesis.[76] "
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    • "Mutations in proteins involved in RNA modifications have been associated previously with preferentially or exclusively either CNS or PNS pathology. For instance, mutations in EXOSC3, TSEN54, TSEN2, and TSEN34 are known to cause neurological phenotypes that manifest in the brain stem and cerebellum, causing Pontocerebellar hypoplasia (PCH) PCH1B, PCH2A, PCH4, PCH2B, and PCH2C, but little is known regarding potential PNS involvement, as the results of nerve conduction studies have not been reported (Budde et al., 2008; Renbaum et al., 2009; Wan et al., 2012). Conversely, mutations in tRNA synthetase genes, such as GARS, KARS, YARS, AARS, and HARS, are predominantly associated with Charcot Marie Tooth neuropathy, distal spinal muscular atrophy, and other PNS disorders without significant CNS involvement (Antonellis et al., 2003; Jordanova et al., 2006; Lee et al., 2006; McLaughlin et al., 2010; Vester et al., 2013). "
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