Bi‐allelic missense variant, p. Ser35Leu in EXOSC1 is associated with pontocerebellar hypoplasia
Open accessAbstract
RNA exosome is a highly conserved ribonuclease complex essential for RNA processing and degradation. Bi-allelic variants in exosome subunits EXOSC3, EXOSC8 and EXOSC9 have been reported to cause pontocerebellar hypoplasia type 1B, type 1C and type 1D, respectively, while those in EXOSC2 cause short stature, hearing loss, retinitis pigmentosa and distinctive facies. We ascertained an 8-months-old male with developmental delay, microcephaly, subtle dysmorphism and hypotonia. Pontocerebellar hypoplasia and delayed myelination were noted on neuroimaging. A similarly affected elder sibling succumbed at the age of 4-years 6-months. Chromosomal microarray returned normal results. Exome sequencing revealed a homozygous missense variant, c.104C > T p.(Ser35Leu) in EXOSC1 (NM_016046.5) as the possible candidate. In silico mutagenesis revealed loss of a polar contact with neighboring Leu37 residue. Quantitative real-time PCR indicated no appreciable differences in EXOSC1 transcript levels. Immunoblotting and blue native PAGE revealed reduction in the EXOSC1 protein levels and EXO9 complex in the proband, respectively. We herein report an individual with the bi-allelic variant c.104C>T p.(Ser35Leu) in EXOSC1 and clinical features of pontocerebellar hypoplasia type 1. Immunoblotting and blue native PAGE provide evidence for the pathogenicity of the variant. Thus, we propose EXOSC1 as a novel candidate gene for pontocerebellar hypoplasia.
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Variants in genes encoding several subunits of the RNA exosome complex have been linked to PCH, including EXOSC3 (PCH1B), EXOSC8 (PCH1C), EXOSC9 (PCH1D), and provisionally EXOSC1 (PCH1F).
“variants in genes encoding several subunits of the RNA exosome complex have been linked to PCH, including EXOSC3 (PCH1B), EXOSC8 (PCH1C), EXOSC9 (PCH1D), and provisionally EXOSC1 (PCH1F)15–25.”
From EXOSC3 G191 Variants Trigger System-Wide Recalibration of RNA Processing Machinery (2026) · cites this paper as [16]
The Introduction links EXOSC3, EXOSC8 and EXOSC9 to subtypes of PCH type 1, and the Discussion proposes EXOSC1 as a candidate gene, supporting the provisional wording. Our copy does not specify the subtype labels PCH1B, PCH1C, PCH1D or PCH1F, so it does not verify those assignments. (LLM, conf=0.84)
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Research works printed but not linked: 17
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Cited by
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EXOSC3 G191 Variants Trigger System-Wide Recalibration of RNA Processing Machinery
Wijeratne, H. R. S., Runnebohm, A. M., Barron, M. P., Hampton, A. J., Li, R., Peck Justice, S. A., Lenceski, S. H., Rooney, J. D., Smith-Kinnaman, W. R., Chang, G. S., et al. (2026) · doi:10.64898/2026.01.26.701775 · Cited by 1 · see citing works
- Authors
- Somashekar, P. H., Kaur, P., Stephen, J., Guleria, V. S., Kadavigere, R., Girisha, K. M., Bielas, S., Upadhyai, P., & Shukla, A.
- Affiliations
- Manipal Academy of Higher Education (IN)
- University of Michigan (US)
- Corresponding author
- Shukla, Anju
- ORCID
- Venue
- Clinical Genetics
- Publisher
- Wiley
- Published
- 2021-01-28
- Volume
- 99
- Issue
- 4
- Pages
- 594-600
- ISSN
- 0009-9163 (ISSN-L)
- 1399-0004
- PMC
- PMC9990822
- OpenAlex
- W3125001317
- Cited by
- 32
- References
- 0
- Citations by year
- 2026: 7 · 2025: 7 · 2024: 5 · 2023: 7 · 2022: 5 · 2021: 1
- FWCI
- 4.45
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Clinical Genetics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Deep Blue (University of Michigan) (submittedVersion)
- Funders
- National Institutes of Health (R01 HD093570 01 A1 (PI))
- Topics
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Fetal and Pediatric Neurological Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- RNA exosome, developmental delay, microcephaly, delayed myelination, hypotonia, variant pathogenicity, novel candidate genes
- MeSH terms
- Exome Sequencing, Alleles, Amino Acid Sequence, Brain, Cerebellar Diseases, Developmental Disabilities, Consanguinity, Humans, Infant, Male, Pedigree, Protein Conformation, Sequence Alignment, RNA-Binding Proteins, Sequence Homology, Amino Acid, Amino Acid Substitution, Mutation, Missense, Exosome Multienzyme Ribonuclease Complex
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