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Am J Hum Genet. Aug 14, 2009; 85(2): 281–289.
PMCID: PMC2725266

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


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.

Main Text

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.1 Proximal SMA (types I–IV [MIM 253300, 253550, 253400, 271150]) accounts for 80%–90% of all SMA cases and is primarily caused by recessive mutations in SMN1 (MIM 600354), with homozygous absence of exon 7 in > 95% of cases.2 Non-SMN1 SMAs include nonproximal SMA (MIM 181405, 182960, 271220, 600794, 605726, 607088, 611067), bulbar palsy (MIM 211500, 211530, 601104), spinobulbar muscular atrophy (SBMA [MIM 313200]), and infantile SMA variants also known as “SMA plus.”1 These variants are characterized by SMA with additional or atypical features. They include SMA with respiratory distress (SMARD [MIM 604320]), which can be caused by recessive mutations in IGHMBP2 (MIM 600502); infantile lethal X-linked SMA with arthrogryposis and congenital fractures (SMAX2 [MIM 301830]), caused by mutations in UBE1 (MIM 314370); SMA1 with arthrogryposis and bone fractures (MIM 271225), which is yet to be mapped; and SMA with pontocerebellar hypoplasia (SMA-PCH [MIM 607596]), also known as PCH type 1. SMA-PCH is also associated with polyhydramnios, congenital contractures (secondary to reduced fetal movement), and respiratory insufficiency, leading to early death (mostly before 1 yr) in the original cases described.3 However, in recent years, a broader clinical spectrum has emerged, with later onset of hypotonia, varying degrees of cerebellar or pontine hypoplasia and atrophy, peripheral nerve involvement, and longer survival.4

SMA-PCH is regarded as a subtype of both SMA and PCH and is also known as PCH1 (MIM 607596). All PCH syndromes include a small cerebellum and brainstem, and progressive microcephaly is common. The six currently described PCH subtypes are distinguished by additional features (OMIM; see Web Resources). SMA is found only in PCH1. PCH2, which is genetically heterogeneous (MIM 277470, 612389, 612390), is characterized by progressive cerebral atrophy, extrapyramidal dyskinesia and chorea, seizures, lack of motor and mental development, and normal spinal cord findings. PCH3 (MIM 608027), mapped to choromosome 7 in a single family, is characterized by optic atrophy, seizures, truncal hypotonia, specific facial features, and lack of extrapyramidal symptoms. PCH4 (MIM 225753) is a severe form with infantile encephalopathy, olivopontine atrophy, and early lethality. In PCH5 (MIM 610204), described in a single family, there is fetal onset of a seizure-like activity and severe olivopontocerebellar hypoplasia. PCH6 is a single-family, fatal, infantile form with mitochondrial respiratory chain defects and lack of motor or mental development. Interestingly, all genes so far identified as mutated in PCH are involved in tRNA processing: PCH2A and PCH4 are caused by TSEN54 (MIM 608755) mutations,5 PCH2B (MIM 612389) is caused by TSEN2 (MIM 608753) mutations,5 and PCH2C (MIM 612390) is caused by TSEN34 (MIM 608754) mutations.5 These genes encode noncatalytic (TSEN54) and catalytic (TSEN2 and TSEN34) subunits of the tRNA splicing endonuclease. PCH6 is caused by mutations in mitochondrial arginyl-tRNA synthetase (RARS2 [MIM 611524]).6

The genetic basis of SMA-PCH has not been determined. The SMN1 locus has been excluded in SMA-PCH, and tRNA defects identified in other forms of PCH during the course of our study were excluded on the basis of genomic location.

We report a consanguineous family of Ashkenazi Jewish origin, including three children with SMA-PCH (Figure 1). The proband (IV-12) was the youngest daughter of first-cousin parents. Pregnancy was remarkable only for microcephaly noted on ultrasound at 7 mo gestation. At birth, weight was 2750 g, head circumference (HC) was 28.5cm (−6 SD), and poor sucking was noted. Brain CT was unremarkable except for microcephaly, and there was no evidence of craniosynostosis on skull X-rays. TORCH serology was negative. HC at 19 mo of age was 38 cm (−7.9 SD). Developmental delay became evident during the first two years (sitting at age 1 yr, assisted walking at 2 yrs), and the proband developed upper limb ataxia, brisk deep tendon reflexes (DTRs), and bilateral equinovarus. Results of electromyography (EMG), nerve conduction velocity (NCV), and somatosensory evoked potential (SEP) studies performed at age 2 yrs were consistent with motor and sensory neuropathy due to chronic denervation, more evident peripherally. Specifically, NCVs were normal, SEP showed diminished sensory nerve action potential (SNAP) in the right sural nerve, and EMG revealed fasciculations and fibrillations, consistent with motor neuron disease. At age 3 yrs, brain MRI showed a small cerebellar vermis and a large cisterna magna, compatible with cerebellar hypoplasia, and spine MRI was normal. (The MRI was performed in 1994 at a private facility, and images are unfortunately unavailable). Concurrently, a sural nerve biopsy was normal and muscle biopsy showed neurogenic atrophy typical of SMA (Figure 2). Cognitive ability was assessed as mild mental retardation. After corrective surgery, the proband began walking independently at age 3 yrs, though with ataxia. Additional studies at age 8 yrs included electron microscopy of a skin biopsy and isoelectric focusing of serum transferrin, which were both normal. Creatine phosphokinase (CPK) was not elevated (40 IU/l), and urinary organic acids were normal. Disease progression led to severe weakness, and the child became wheelchair-bound and incontinent, with sleep disturbance, increasing swallowing difficulties, severe ataxia, and progressive intercostal muscle weakness. A percutaneous gastrostomy was performed to allow feeding, but a few days after this procedure, the proband died at age 11.5 yrs. Testing for deletion of exon 7 in SMN1 was negative.

Figure 1
Linkage and Homozygosity Mapping of Markers on 14q32 to SMA-PCH in a Consanguineous Family
Figure 2
Muscle Biopsy of the Proband at Age 3 Yrs

The proband had a previously deceased older sister (IV-6) who was treated at another institution for the same condition. Review of her clinical records showed that after a normal pregnancy, birthweight was 3100 g and microcephaly was noted (HC 30.5 cm [−3 SD]). Investigations for microcephaly included skull X-rays, optic fundi examination, and TORCH serology, all of which were normal. She gained weight slowly but was otherwise healthy. Delayed motor milestones were apparent in the first year (rolling over at 8 mo, sitting at 15 mo, standing at 18 mo). Early language and social skills developed appropriately. Investigations at 6 mo included repeated skull X-rays demonstrating closure of skull sutures. EEG showed abnormal generalized discharges. Auditory brainstem response (ABR), visual evoked potential (VEP), and electroretinography (ERG) were normal. Brain CT scan showed mild bilateral enlargement of the posterior horns of the lateral ventricles, a large cisterna magna, and minimal cortical atrophy. Neurological examination at 2 yrs showed tongue fasciculations, hypotonia with brisk DTRs, and ataxia. Concurrently, she was noted to have bilateral equinovarus deformities, which necessitated splinting. At age 3 yrs, she was enrolled in a special education program. General functioning was severely impaired by ataxia, but language comprehension and social skills were relatively spared. At age 5 yrs, she could crawl on her knees independently and walk with the aid of a walker and braces. Examination revealed progressive microcephaly (HC 42.5cm [−6 SD]), distal muscle atrophy, brisk DTRs, no nystagmus, and obvious hand tremor and ataxia. EMG and NCV at this time showed demyelinating peripheral neuropathy. CSF protein (age 6 yrs) was 24 mg%. Brain CT scan at age 7 yrs showed cerebellar hypoplasia with suspected pontine hypoplasia (Figure 3). A CT of the cervical spine was normal. Additional laboratory tests showed normal female karyotype (46,XX), negative urinary oligosaccharides, and normal activity levels of the following lysosomal enzymes: Hexosaminidase A (Tay-Sachs disease [MIM 272800]), Galactocerebrosidase (Krabbe disease [MIM 245200]), Arylsulfatase A (metachromatic leukodystrophy [MIM 250100]), and beta-Galactosidase 1 (GM1 gangliosidosis [MIM 230500]). At age 8 yrs, incontinence developed, muscle strength decreased, and she became nonambulatory. Sleep disturbances appeared and progressed, with frequent awakenings. At age 9 yrs, a percutaneous gastrostomy was inserted because of increasing feeding and swallowing difficulties. A muscle biopsy performed at that time revealed neurogenic atrophy typical of SMA. Her disease progressed and she died at age 9.5 yrs. The family refused autopsy for both daughters. To summarize, both sisters presented with motor neuron disease consistent with SMA: clinically prominent progressive muscular weakness, EMG reflecting chronic denervation (fasciculations and fibrillations), and typical muscle pathology (neurogenic atrophy; see Figure 2). Both had progressive microcephaly of prenatal onset, mental deficiency, and significant ataxia, correlated with cerebellar hypoplasia on brain imaging (Figure 3). There were equivocal features of sensory neuropathy and evidence for upper motor neuron involvement. The disease was progressive from infancy but protracted, with death at 9.5 and 11.5 years. Notably, both girls had normal birth weights and did not have congenital arthrogryposis. The disease process was symmetric; there were no seizures, dykinesia, or chorea and no evidence of severe respiratory distress or diaphragmatic dysfunction. Both sisters were independently diagnosed with SMA-PCH, by two different clinical teams. Their cousin (IV-14), also the product of a consanguineous marriage within the extended family, was reported by his parents to have had a similar phenotype. He died at age 8 yrs, and his medical records are unavailable.

Figure 3
Brain CT Scan of the Proband's Sister at Age 7 Yrs, in 1989

After approval by an institutional review board and the National Helsinki Committee for Genetic Studies, homozygosity mapping was performed on the proband (IV-12), who was the single affected individual for whom DNA was available, and on all other available relatives (Figure 1). DNA isolated from blood was typed with the use of the Affymetrix GeneChip 250K Nsp SNP array. SNP data were examined for informative genomic regions that were longer than 5 Mb and homozygous in the proband but not in any of her healthy siblings. Boundaries of homozygous segments in the proband were defined by the presence of two heterozygous SNPs in any moving 10-SNP window. A single 6.24 Mb region on chromosome 14 (including 576 SNPs from rs7146008 at 90,663,054 to rs17095290 at 96,905,397) was identified as homozygous by descent only in the affected proband. In addition, linkage analysis on genome-wide SNP data was performed with the use of Superlink Online,7,8 assuming autosomal-recessive inheritance of SMA-PCH, high penetrance (99%), rare frequency of the disease allele in the general population (0.001), and no phenocopies. A multipoint LOD score of 3.3 was obtained for a 200 kb interval within the 6.24 Mb chromosome 14 homozygous region. No other region fulfilled homozygosity criteria or had significant LOD scores. Fine mapping of the homozygous region with the use of short tandem repeat (STR) markers defined a minimal 6.04 Mb interval between D14S995 (cen) and D14S65 (tel) (Figure 1), a region containing 71 known and predicted genes (UCSC Genome Browser).

An obvious candidate gene in this region was Ataxin-3 (ATXN3), because expansion of a coding CAG repeat in ATXN3 causes spinocerebellar ataxia type 3 (SCA3 or Machado-Joseph disease [MJD, MIM 109150]).9 MJD is an autosomal-dominant, adult-onset disease, whereas SMA-PCH is an autosomal-recessive disease of prenatal or infantile onset, but the cerebellum and spinocerebellar tracts are major targets of both diseases, so conceivably, a recessive ATXN3 mutation could lead to SMA-PCH. We examined this possibility as follows (data not shown): (1) All ATXN3 exons (including 5′ and 3′ UTRs) were sequenced in both parents and the affected proband in both directions. No previously unreported variants were identified. (2) ATXN3 CAG repeats were genotyped in the entire family (ATXN3-CAG, Figure 1), and no expansion was identified. (3) For the purpose of ruling out a nonexonic mutation affecting ATXN3 regulation, allele-specific ATXN3 expression was analyzed in cDNA from lymphoblastoid cell lines of both parents. Both parents (obligate carriers) were heterozygous for a known SNP (rs12895357) in exon 10 and for the ATXN3 CAG repeat. Semiquantitative RT-PCR revealed comparable biallelic expression of ATXN3 in both assays in each parent. (4) ATXN3 splicing patterns were tested in both parents and in unrelated control individuals. No differences were observed in six different RT-PCR amplicons spanning the entire ATXN3 transcript. Other genes in the minimal homozygous region were prioritized on the basis of cerebellar and spinal cord expression via the use of publicly available data on tissue-specific expression (Genecards) and RT-PCR on human cerebellar RNA (Ambion, TX, USA). In addition, we assessed known human phenotypes and murine models of genes in the candidate region. The proband's DNA was fully sequenced for 27 genes in the region, and no mutations were found (Table 1).

Table 1
The SMA-PCH Chromosome 14 Homozygous Region—Genes Sequenced and Found to be Wild-Type in the Affected Proband

In the VRK1 (vaccinia related kinase) gene (MIM 602168), the proband was found to have a homozygous C>T transition in nt 4 of VRK1 exon 12 (NM_003384, 1072 C>T; chr14:96,412,123 on hg18, NCBI Build 36.1, displayed on the UCSC Genome Browser), creating a stop codon (R358X) (Figure 4A) within a highly conserved KKRKK nuclear localization signal (NLS) (Figures 4B and 4C). Semiquantitative comparison of the expression patterns of mutant and wild-type alleles in the heterozygous parents suggests that the mutant sequence is associated with significantly lower mRNA levels than the wild-type, perhaps as a result of nonsense-mediated decay (Figure 4D). Familial segregation of the mutation was as expected, revealing that the proband's aunt (III-3) and uncle (III-4) are indeed both carriers of VRK1 R358X.

Figure 4
Homozygous VRK1 Nonsense Mutation in SMA-PCH

VRK1 exon 12 was sequenced in 449 normal Ashkenazi Jewish controls, and two VRK1 R358X carriers were identified. The allele frequency is therefore 1/449 (95% CI: 1/625–1/263), confirming the rarity of the SMA-PCH mutation.

VRK1 was originally identified as a novel serine-threonine kinase in a screen for genes enriched in fetal versus adult liver and involved in cell cycle regulation.10 The VRK1 gene (NM_003384) comprises 13 exons encoding a 1720 nt transcript, including a 106 bp 5′ UTR and a 423 bp 3′ UTR. VRK1 encodes a 396 aa protein (NP_003375), with an N-terminal serine/threonine kinase domain (aa 173–185), a C-terminal NLS (residues 356–360), an endosomal and lysosomal targeting sequence (aa 304–320), and a basic-acidic-basic (BAB) motif at the C terminus (Figure 4B). Through homology searches, the mammalian VRK family was found to include two additional members: VRK2, which associates with the endoplasmic reticulum (ER) and the nuclear envelope (NE) and is enzymatically active, and VRK3, which is nuclear and enzymatically inactive as a result of key amino acid substitutions.10,11 C. elegans and Drosophila have a single VRK ortholog, CeVRK1 and NHK1, respectively.

VRK1 is ubiquitously expressed, including in fetal and adult brain and cerebellum (10 and data not shown). At the subcellular level, it is mainly a nuclear protein, with a small fraction found in the cytoplasm and membrane compartments11,12 (Human Protein Atlas). Dynamics of subcellular localization have not been studied in mammals, but in Drosophila and C. elegans, localization is cell-cycle-dependent: NHK-1 is cytoplasmic in the S phase, binds condensing chromatin in prophase, and is excluded from chromatin at the end of mitosis.13 CeVRK-1 relocates to the nuclear rim just before mitosis and binds to chromatin from nuclear envelope breakdown until the end of mitosis.14

VRK1 function has been most extensively studied in the context of cellular proliferation and tumorigenesis (reviewed in 15). VRK1 stabilizes p53 by phosphorylating its transactivation domain, thereby preventing its interaction with Mdm2. Normally, increased p53 proteolytically downregulates VRK1, but this autoregulatory loop is disrupted in a number of tumors, where increased VRK1 levels correlate with proliferation markers.16 VRK1 also phosphorylates other transcription factors, including c-JUN, ATF-2, and CREB, and has recently been shown to be an early-response gene required for G1/S cell cycle progression,17,18 at least in part through CREB-mediated regulation of cyclin D1 expression.18 Identification of Myc as an activator of VRK1 expression is further evidence of its significance for cellular proliferation.18 In addition to these functions, VRK1 plays an important role in nuclear envelope and chromatin organization. VRK1 phosphorylates histone H3 during mitosis, and VRK inactivation in C. elegans and Drosophila results in chromatin hypercondensation.19 In the nuclear envelope, VRK1 is essential for formation of nuclear membrane pore complexes, at least in part through its interaction with BAF (barrier to autointegration factor).14 VRK1 phophorylates BAF during mitosis, thus releasing it from chromatin, to which it is bound during interphase.14,20 BAF release is accompanied by release of nuclear lamina proteins, including emerin, a release critical for NE assembly. Lack of the single VRK gene in Drosophila is lethal.21

Our results suggest that in humans, VRK1 deficiency causes a neurological phenotype that is both developmental and degenerative. Known VRK1 functions suggest interesting possibilities for its role in nervous system development and neuronal maintenance. Although VRK1 has not been studied in this context, in mice, VRK1 is expressed in the brain and spinal cord in all stages of development, including the adult (Allen Brain Atlas and data not shown). The VRK1/p53 autoregulatory loop may be relevant not only for malignancy but also for development and maintenance of the nervous system. p53 regulates cell division and death during nervous system development and in response to neuronal insult or injury during life (reviewed in 22). Recessive mutations in ATM, which phosphorylates p53 in response to DNA damage, cause ataxia telangiectasia (MIM 208900), in which loss of cerebellar neurons and ataxia are prominent features. p53 interacts directly with SMN1, an association disrupted by SMN1 mutations associated with SMA,23 although the relevance of this interaction to SMA pathogenesis is unclear.24 Its role in the nuclear envelope may link VRK1 defects to the laminopathies, which have neuromuscular manifestations (reviewed in 25). With respect to the essential role of VRK1 in BAF function, Baf null flies have small brains, missing imaginal discs, and defects in cell proliferation and differentiation in the thoracic ganglia and the brain hemispheres.26 The role of VRK1 in CREB activation suggests that VRK1 mutations may lead to impaired CREB signaling, which can result in both developmental and degenerative neurological disease. Coffin Lowry syndrome (MIM 303600) is caused by mutations in RSK2, another CREB kinase. Rubinstein Taybi syndrome (MIM 180849) can be caused by mutations in CREBBP, a CREB-binding protein. CREB depletion in the postnatal mouse brain leads to progressive neurodegeneration,27 and interference with CREB-dependent transcription is a feature of polyglutamine stretches, common in spinocerebellar ataxias.28 CREB also binds to the SMN promoter and increases SMN expression, so its deficiency could promote an SMA phenotype.29

As in any identification of a gene for a rare recessive disease in a single family, we cannot exclude the possibility of a deleterious mutation in one of the genes in the region that were not sequenced in the proband. However, the presence of a homozygous null mutation suggests that VRK1 is very highly likely to be an SMA-PCH gene. Verification would require identification of additional patients with VRK1 mutations and additional studies addressing the mechanisms by which VRK1 mutation leads to neuronal disease. Previous genes implicated in PCH without SMA are all involved in tRNA processing,5,6 suggesting that VRK1 may be specifically important for spinal motor neuron survival or that it may also play a role in tRNA processing. In either case, identification of a VRK1 mutation as a cause of SMA-PCH points to new roles for this protein and suggests VRK2 (chromosome 2p16) and VRK3 (chromosome 19q13) as candidate genes for related phenotypes, including other pontocerebellar hypoplasias and other spinal muscular atrophies.


We thank Tom D. Bird of the Departments of Medicine and Neurology at the University of Washington, Seattle, WA, for reviewing the clinical information on the patients described in the study. Shirley Horn-Saban, Head of the Microarray Facility at the Weizmann Institute of Science, Rehovot, Israel, performed SNP genotyping. We thank Anna Tzemach for assistance with the genome-wide linkage analysis. We thank Hadassah Hartman for excellent secretarial assistance, and we thank all family members for their participation in this study. This research was supported by the Legacy Heritage Bio-Medical Program of the Israel Science Foundation (grant no. 1872/2008 to P.R. and E.L.L.), by the Israel Science Foundation (grant no. 1174/2007 to D.G.), and by a generous gift from Rabbi and Mrs. David Fuld to Shaare Zedek Medical Center.

Web Resources

The URLs for data presented herein are as follows:


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