VRK1 – Pontocerebellar Hypoplasia Type 1

Pontocerebellar hypoplasia type 1 (PCH1) is an autosomal recessive neurodevelopmental disorder characterized by hypoplasia of the cerebellum and pons, antenatal‐onset microcephaly, and motor neuron degeneration. While mutations in EXOSC3, SLC25A46, and EXOSC8 account for many PCH1 cases, rare VRK1 variants have been implicated in a milder PCH1 phenotype with extended survival and upper motor neuron signs (PMID:29656927).

Autosomal recessive VRK1‐associated PCH1 has been documented in a founder Ashkenazi Jewish proband homozygous for c.1072C>T (p.Arg358Ter) (PMID:25609612). Additional VRK1‐deficient patients exhibit SMA‐like presentations with microcephaly, dystonia, and ataxia, although familial segregation data remain limited.

Functional studies demonstrate that VRK1‐R358X homozygosity leads to complete loss of VRK1 protein, impairing cortical neuronal migration and progenitor proliferation in mouse in utero electroporation assays. Wild‐type VRK1 rescues both proliferation and migration phenotypes, whereas kinase‐dead VRK1 rescues migration alone, indicating a partly noncatalytic role mediated via downregulation of amyloid-β precursor protein (PMID:25609612).

In vrk1–/– zebrafish, complete absence of VRK1 causes mild microcephaly, motor dysfunction, reduced brain dopamine, and impaired neuronal proliferation and nuclear envelope integrity, recapitulating key human features of PCH1 and underscoring a loss-of-function mechanism (PMID:37429068).

Collectively, these data support VRK1 haploinsufficiency as a pathogenic mechanism in a subset of PCH1 cases, with robust in vivo and in vitro concordance. Further identification of additional VRK1 families and segregation analyses will refine penetrance estimates and continuum with other motor neuron disorders.

Key Take-home: VRK1 loss-of-function variants cause a distinct, autosomal recessive PCH1 phenotype, warranting inclusion of VRK1 in diagnostic gene panels for Pontocerebellar hypoplasia type 1.

References

• European journal of paediatric neurology • 2018 • Pontocerebellar hypoplasia type 1 for the neuropediatrician: Genotype-phenotype correlations and diagnostic guidelines based on new cases and overview of the literature. PMID:29656927
• The Journal of neuroscience • 2015 • The spinal muscular atrophy with pontocerebellar hypoplasia gene VRK1 regulates neuronal migration through an amyloid-β precursor protein-dependent mechanism PMID:25609612
• Biochemical and biophysical research communications • 2023 • Behavioral and neurological effects of Vrk1 deficiency in zebrafish. PMID:37429068

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