Mutations inVRK1Associated With Complex Motor and Sensory Axonal Neuropathy Plus Microcephaly

Abstract

IMPORTANCE Patients with rare diseases and complex clinical presentations represent a challenge for clinical diagnostics. Genomic approaches are allowing the identification of novel variants in genes for very rare disorders, enabling a molecular diagnosis. Genomics is also revealing a phenotypic expansion whereby the full spectrum of clinical expression conveyed by mutant alleles at a locus can be better appreciated.OBJECTIVE To elucidate the molecular cause of a complex neuropathy phenotype in 3 patients by applying genomic sequencing strategies. DESIGN, SETTING, AND PARTICIPANTS Three affected individuals from 2 unrelated families presented with a complex neuropathy phenotype characterized by axonal sensorimotor neuropathy and microcephaly. They were recruited into the Centers for Mendelian Genomics research program to identify the molecular cause of their phenotype. Whole-genome, targeted whole-exome sequencing, and high-resolution single-nucleotide polymorphism arrays were performed in genetics clinics of tertiary care pediatric hospitals and biomedical research institutions. MAIN OUTCOMES AND MEASURESWhole-genome and whole-exome sequencing identified the variants responsible for the patients' clinical phenotype. RESULTSWe identified compound heterozygous alleles in 2 affected siblings from 1 family and a homozygous nonsense variant in the third unrelated patient in the vaccinia-related kinase 1 gene (VRK1). In the latter subject, we found a common haplotype on which the nonsense mutation occurred and that segregates in the Ashkenazi Jewish population. CONCLUSIONS AND RELEVANCEWe report the identification of disease-causing alleles in 3 children from 2 unrelated families with a previously uncharacterized complex axonal motor and sensory neuropathy accompanied by severe nonprogressive microcephaly and cerebral dysgenesis. Our data raise the question of whether VRK1 mutations disturb cell cycle progression and may result in apoptosis of cells in the nervous system. The application of unbiased genomic approaches allows the identification of potentially pathogenic mutations in unsuspected genes in highly genetically heterogeneous and uncharacterized neurological diseases.

The Spinal Muscular Atrophy with Pontocerebellar Hypoplasia GeneVRK1Regulates Neuronal Migration through an Amyloid-β Precursor Protein-Dependent Mechanism

“…We hypothesized a role for VRK1 in neuronal migration based on brain MRIs of affected children ( Fig. 1A-D ;Gonzaga-Jauregui et al, 2013) and the observed effect of the mutation on expression of genes associated with the Reelin pathway. Our results also suggested that VRK1 R358X is a null allele, and furthermore, any residual mutant protein that may be produced will not enter the nucleus .…”

“…Pathway analysis showed that the Reelin signaling was the pathway most significantly associated with expression differences in VRK1-mutant cells ( p Ͻ 0.002; Table 1). Reelin signaling is required for proper positioning of neurons within the laminated telencephalon (Rice and Curran, 2001;Frotscher et al, 2009), and also plays a role in neuronal migration in the spinal cord (Yip et al, 2009). The association of altered Reelin pathway expression and the simplified gyral patterns observed in brain MRIs of affected individuals ( Fig.…”

“…SMA-PCH [or pontocerebellar hypoplasia type 1A (PCH1A) MIM (Mendelian Inheritance in Man) #607596], is an infantile SMA variant with additional manifestations, including severe congenital microcephaly, mental retardation, and cerebellar signs (Barth, 1993;Rudnik-Schöneborn et al, 2003). We identified a vaccinia-related kinase 1 (VRK1) nonsense mutation (R358X) as a cause of SMA-PCH in a consanguineous Ashkenazi Jewish family and other cases have since been reported (Gonzaga-Jauregui et al, 2013). VRK1-R358X is a rare founder allele: carrier frequency in Ashkenazi Jews is ϳ1/ 250 (Renbaum et al, 2009).…”

“…VRK1-R358X is a rare founder allele: carrier frequency in Ashkenazi Jews is ϳ1/ 250 (Renbaum et al, 2009). Other VRK1 mutations have been reported: homozygosity for VRK1-R133C in Iranian siblings with SMA-PCH (Najmabadi et al, 2011), and compound heterozygosity for VRK1 V236M and R89Q in two sisters with microcephaly and complex motor and sensory axonal neuropathy (Gonzaga-Jauregui et al, 2013).…”

VRK1 chromatin kinase phosphorylates H2AX and is required for foci formation induced by DNA damage

“…29,30 Pathologically, human VRK1 mutations are very rare and are manifested as complex neurodegenerative syndromes in children, in which pontocerebellar hypoplasia, microcephaly, muscular atrophy, and ataxia are components of their clinical phenotype. 31,32 Similarly, many hereditary mutations in DNA repair genes are also clinically manifested as neurodegenerative diseases in children. 33 Gene transcription requires dynamic local remodeling of chromatin.…”