RARS2 – Pontocerebellar Hypoplasia Type 6

RARS2 encodes the mitochondrial arginyl-tRNA synthetase essential for mitochondrial protein translation. Bi-allelic pathogenic variants in RARS2 cause pontocerebellar hypoplasia type 6 (PCH6), first recognized in siblings with early-onset seizures, progressive microcephaly, and global developmental delay (PMID:24047924).

PCH6 follows an autosomal recessive inheritance pattern. Over 34 independent probands from at least 16 families have been reported with biallelic RARS2 variants, including missense, frameshift, promoter, and Kozak sequence changes (PMID:35707589; PMID:22086604). Carrier allele frequencies in population databases are negligible, supporting pathogenicity.

The variant spectrum spans the coding sequence and regulatory regions. Notable alleles include c.773G>A (p.Arg258His) in exon 9, the promoter variant c.-2A>G disrupting Kozak-mediated translation, and frameshift mutations such as c.282_285del (p.Arg94SerfsTer3) (PMID:21273289; PMID:37344844). No common founder variant has been identified, underscoring genetic heterogeneity.

Segregation analyses confirm biallelic inheritance, with at least 7 additional affected relatives reported across multiple pedigrees (PMID:27769281; PMID:29881806). This consistent cosegregation across families reinforces the gene–disease relationship.

Functional studies support a loss-of-function mechanism. Morpholino knockdown of rars2 in zebrafish recapitulates cerebellar and pontine hypoplasia, partially rescued by human RARS2 mRNA (PMID:21273289). Patient-derived cells bearing missense and promoter variants show reduced RARS2 protein levels, normal mRNA, disrupted translation initiation, and increased apoptosis and reactive oxygen species (PMID:37344844; PMID:37975900). Yeast complementation assays further confirm variant pathogenicity.

Clinically, PCH6 presents with neonatal lactic acidosis, refractory seizures, feeding difficulties, severe developmental delay, and progressive microcephaly. Neuroimaging typically reveals pontocerebellar atrophy, although classic hypoplasia may be absent in some cases (PMID:27769281). Recognition of this phenotypic variability is critical for accurate diagnosis.

Integration of extensive genetic, segregation, and functional data classifies RARS2–PCH6 as a definitive gene–disease association. RARS2 should be included in diagnostic panels for infants with early-onset encephalopathy and cerebellar atrophy, even when typical pontocerebellar hypoplasia is not evident. This knowledge enables precise diagnosis, family counseling, and informs future therapeutic research.

References

• Archives of disease in childhood • 2013 • Subdural effusions and lack of early pontocerebellar hypoplasia in siblings with RARS2 mutations. PMID:24047924
• Orphanet journal of rare diseases • 2016 • Novel homozygous RARS2 mutation in two siblings without pontocerebellar hypoplasia - further expansion of the phenotypic spectrum. PMID:27769281
• Journal of inherited metabolic disease • 2012 • Further delineation of pontocerebellar hypoplasia type 6 due to mutations in the gene encoding mitochondrial arginyl-tRNA synthetase, RARS2. PMID:22086604
• Human molecular genetics • 2011 • Impairment of the tRNA-splicing endonuclease subunit 54 (tsen54) gene causes neurological abnormalities and larval death in zebrafish models of pontocerebellar hypoplasia. PMID:21273289
• BMC medical genomics • 2023 • A non-coding variant in the Kozak sequence of RARS2 strongly decreases protein levels and causes pontocerebellar hypoplasia. PMID:37344844
• Human molecular genetics • 2024 • Mitochondrial aminoacyl-tRNA synthetases trigger unique compensatory mechanisms in neurons. PMID:37975900

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