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: 10.99). 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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    • "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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    • "We also examined the effect of the double mutant VRK1 (E313G/K314I), a locally charged region of the VRK1 C-terminus, on the interaction (Fig. S2A and B) and we found that a change in the charge in this region resulted in increased binding. Noteworthy, when the mutation that causes spinal muscular atrophy, VRK1(R358X) [50], was tested we showed that VRK1 was still able to interact with p53 "
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    • "Qualitative and quantitative changes in the coding exons of genes associated with more common forms of PCH — namely, subunits of the TSEN complex (Budde et al 2008) and VRK1 (Renbaum et al 2009) —, progressive cerebellocerebral atrophy (PCCA) ( SepSecS ; Agamy et al 2010) or severe mitochondrial progressive encephalopathy of infancy Fig. 2 Coronal and sagittal T1 weighted images corresponding to patients A-01 (a, b) and B-02 (c), performed within the age of 1 month exemplifying the range of neuroimage severity of early cerebellar involvement from clear cerebellar hypoplasia/atrophy (a, b) to normal aspect (c). Brain MR-S of patient B-02 (d). "
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