EXOSC3 – Pontocerebellar Hypoplasia Type 1B

Pontocerebellar hypoplasia type 1B (PCH1B) is an autosomal recessive neurodegenerative disorder caused by biallelic mutations in EXOSC3, encoding a core subunit of the RNA exosome complex. Affected individuals universally display cerebellar hypoplasia, pontine atrophy, spinal motor neuron degeneration, and early‐onset neuromuscular dysfunction. Recurrent and novel EXOSC3 variants have been reported across five unrelated families, establishing a consistent gene–disease relationship.

Genetic evidence includes 9 probands across 5 families and segregation in 4 additional affected relatives, with homozygous and compound heterozygous presentations (PMID:28687512, PMID:30986545, PMID:35990027, PMID:37337484, PMID:33462000). The variant spectrum comprises four recurrent missense changes (p.Asp132Ala, p.Gly31Ala, p.Trp238Arg, p.Gly191Asp) and multiple frameshift alleles (e.g., p.Ser140fs, p.Pro52fs), reflecting both hypomorphic and loss‐of‐function mechanisms. A key founder allele c.395A>C (p.Asp132Ala) segregates with a milder phenotype in homozygotes, whereas compound heterozygotes and other missense or truncating variants often lead to lethal neonatal presentations.

Clinical features characteristically include progressive microcephaly (HP:0000253), cerebellar atrophy (HP:0001272), severe muscular hypotonia (HP:0006829), respiratory distress (HP:0002098), multiple joint contractures (HP:0002828), and cerebellar hypoplasia (HP:0001321), with variable intrafamilial expressivity and survival ranging from neonatal death to adolescence.

Functional studies in patient fibroblasts revealed mislocalization of EXOSC3 to the cytosol, reduced mtDNA copy number, and secondary mitochondrial complex I and PDHc deficiencies (PMID:28687512). Yeast modeling of EXOSC3‐equivalent substitutions demonstrated that p.Gly31Ala and p.Asp132Ala maintain basic exosome function, whereas p.Trp238Arg (Rrp40‐W195R) destabilizes the exosome, impairs RNA degradation, and hinders cell growth (PMID:27777260, PMID:28053271).

A zebrafish chemical biology approach identified a small molecule (ERD03) that reproduces PCH1B‐like cerebellar hypoplasia and RNA expression changes, underscoring the critical role of EXOSC3–RNA interactions in cerebellar development (PMID:30141626).

Overall, the genetic and experimental data achieve a Strong ClinGen classification for EXOSC3–PCH1B association, with concordant segregation, variant recurrence, and functional concordance. Further natural history studies and high‐throughput functional assays are warranted to refine genotype–phenotype correlations. Key take‐home: EXOSC3 sequencing and targeted panels are clinically indicated for infants presenting with cerebellar hypoplasia, motor neuron degeneration, and early neuromuscular failure.

References

• Mitochondrion • 2017 • Recessive mutation in EXOSC3 associates with mitochondrial dysfunction and pontocerebellar hypoplasia. PMID:28687512
• European journal of medical genetics • 2020 • Novel EXOSC3 pathogenic variant results in a mild course of neurologic disease with cerebellum involvement. PMID:30986545
• Journal of pediatric genetics • 2022 • Retrospective Diagnosis of Pontocerebellar Hypoplasia Type 1B in a Family with Two Deceased Newborn Children. PMID:35990027
• Cureus • 2023 • Homozygous EXOSC3 c.395A>C Variants in Pontocerebellar Hypoplasia Type 1B: A Sibling Pair With Childhood Lethal Presentation and Literature Review. PMID:37337484
• BMJ case reports • 2021 • Two siblings with a novel variant of EXOSC3 extended phenotypic spectrum of pontocerebellar hypoplasia 1B to an exceptionally mild form. PMID:33462000
• Genetics • 2017 • Insight into the RNA Exosome Complex Through Modeling Pontocerebellar Hypoplasia Type 1b Disease Mutations in Yeast. PMID:27777260
• RNA (New York, N.Y.) • 2017 • Mutations of EXOSC3/Rrp40p associated with neurological diseases impact ribosomal RNA processing functions of the exosome in S. cerevisiae. PMID:28053271
• ACS chemical biology • 2018 • A Chemical Biology Approach to Model Pontocerebellar Hypoplasia Type 1B (PCH1B). PMID:30141626

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