RNASEH2B – Aicardi-Goutieres Syndrome Type 2

Aicardi-Goutieres syndrome type 2 (AGS2) is an early-onset, autosomal recessive encephalopathy characterized by progressive microcephaly, spasticity, spastic tetraplegia, anarthria, and cognitive impairment. Four unrelated probands have been reported with biallelic RNASEH2B variants, including two siblings homozygous for c.529G>A (p.Ala177Thr) (PMID:28762473), a compound heterozygote with one novel missense and one frameshift allele (PMID:33981319), and a patient carrying an intronic splice variant c.322-17A>G (PMID:36775013), supporting disease causality under an autosomal recessive inheritance model.

Segregation analysis demonstrated co-segregation of the homozygous p.Ala177Thr allele in a consanguineous family with two affected siblings (PMID:28762473), yielding segregation evidence in one kindred with two affected relatives. Case reports also document recurrent homozygous p.Ala177Thr and compound heterozygous configurations in unrelated families.

Functional studies reveal that p.Ala177Thr and p.Val185Gly substitutions in recombinant RNase H2B result in reduced heterotrimer stability and diminished enzymatic activity compared to wild type (PMID:31529068). Patient cells carrying these variants exhibit decreased RNASEH2B transcript and protein levels, intronic retention leading to premature termination (PMID:36775013), and an upregulated type I interferon signature consistent with AGS pathogenesis (PMID:29030706).

No significant conflicting reports have been identified. The collective genetic data are limited by a small number of probands and segregation in only one family, though functional concordance across in vitro and patient studies is robust.

Taken together, RNASEH2B exhibits a Limited but substantiated association with AGS2, mediated by loss-of-function mechanisms and innate immune activation. Additional well-characterized pedigrees and natural history studies would strengthen the clinical validity.

Key Take-home: RNASEH2B genotyping is clinically useful for early diagnosis of AGS2 and guiding targeted management as novel therapies emerge.

References

• Developmental medicine and child neurology • 2017 • Late diagnosis and atypical brain imaging of Aicardi-Goutieres syndrome: are we failing to diagnose Aicardi-Goutieres syndrome PMID:28762473
• Frontiers in immunology • 2021 • Case Report: Novel Compound Heterozygous RNASEH2B Mutations Cause Aicardi-Goutieres Syndrome PMID:33981319
• European journal of medical genetics • 2023 • Molecular characterization of an intronic RNASEH2B variant in a patient with Aicardi-Goutieres syndrome PMID:36775013
• Journal of biochemistry • 2019 • Characterization of six recombinant human RNase H2 bearing Aicardi-Goutieres syndrome causing mutations PMID:31529068
• Acta neuropathologica • 2017 • Rare ADAR and RNASEH2B variants and a type I interferon signature in glioma and prostate carcinoma risk and tumorigenesis PMID:29030706

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