Novel EXOSC9 variants cause pontocerebellar hypoplasia type 1D with spinal motor neuronopathy and cerebellar atrophy

Sakamoto, Masamune; Iwama, Kazuhiro; Sekiguchi, Futoshi; Mashimo, Hideaki; Kumada, Satoko; Ishigaki, Keiko; Okamoto, Nobuhiko; Behnam, Mahdiyeh; Ghadami, Mohsen; Koshimizu, Eriko; Miyatake, Satoko; Mitsuhashi, Satomi; Mizuguchi, Takeshi; Takata, Atsushi; Saitsu, Hirotomo; Miyake, Noriko; Matsumoto, Naomichi

doi:10.1038/s10038-020-00853-2

Cited by 26Fetal and Pediatric Neurological DisordersGenomics and Rare DiseasesGenetics and Neurodevelopmental Disorders

Novel EXOSC9 variants cause pontocerebellar hypoplasia type 1D with spinal motor neuronopathy and cerebellar atrophy

Sakamoto, Masamune, Iwama, Kazuhiro, Sekiguchi, Futoshi, Mashimo, Hideaki, Kumada, Satoko, Ishigaki, Keiko, Okamoto, Nobuhiko, Behnam, Mahdiyeh +9 more·2021·Journal of Human Genetics

DOI 10.1038/s10038-020-00853-2

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Abstract

Pontocerebellar hypoplasia (PCH) is currently classified into 13 subgroups and many gene variants associated with PCH have been identified by next generation sequencing. PCH type 1 is a rare heterogeneous neurodegenerative disorder. The clinical presentation includes early-onset severe developmental delay, progressive motor neuronopathy, and cerebellar and pontine atrophy. Recently two variants in the EXOSC9 gene (MIM: 606180), NM_001034194.1: c.41T>C (p.Leu14Pro) and c.481C>T (p.Arg161*) were identified in four unrelated patients with PCH type 1D (PCH1D) (MIM: 618065). EXOSC9 encodes a component of the exosome complex, which is essential for correct processing and degradation of RNA. We report here two PCH1D families with biallelic EXOSC9 variants: c.239T>G (p.Leu80Arg) and c.484dupA (p.Arg162Lysfs*3) in one family and c.151G>C (p.Gly51Arg) in the other family. Although the patients studied here showed similar clinical features as previously described for PCH1D, relatively greater intellectual development (although still highly restricted) and normal pontine structure were recognized. Our findings expand the clinical consequences of biallelic EXOSC9 variants.

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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 [17]

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Authors: Sakamoto, M., Iwama, K., Sekiguchi, F., Mashimo, H., Kumada, S., Ishigaki, K., Okamoto, N., Behnam, M., Ghadami, M., Koshimizu, E., Miyatake, S., Mitsuhashi, S., Mizuguchi, T., Takata, A., Saitsu, H., Miyake, N., & Matsumoto, N.
Affiliations: Yokohama City University (JP)
Tokyo Metropolitan Neurological Hospital (JP)
Tokyo Women's Medical University (JP)
Osaka Women's and Children's Hospital (JP)
Isfahan University of Medical Sciences (IR)
Tehran Heart Center (IR)
Yokohama City University Hospital (JP)
Hamamatsu University School of Medicine (JP)
Corresponding author: Miyake, Noriko
Matsumoto, Naomichi
ORCID: Sakamoto, Masamune
Iwama, Kazuhiro
Kumada, Satoko
Ishigaki, Keiko
Okamoto, Nobuhiko
Behnam, Mahdiyeh
Ghadami, Mohsen
Koshimizu, Eriko
Miyatake, Satoko
Mitsuhashi, Satomi
Mizuguchi, Takeshi
Takata, Atsushi
Saitsu, Hirotomo
Miyake, Noriko
Matsumoto, Naomichi
Venue: Journal of Human Genetics
Publisher: Springer Science and Business Media LLC
Published: 2020-10-10
Volume: 66
Issue: 4
Pages: 401-407
ISSN: 1434-5161 (ISSN-L)
1435-232X
DOI: 10.1038/s10038-020-00853-2
OpenAlex: W3092282356
Cited by: 26
References: 7
Citations by year: 2026: 5 · 2025: 4 · 2024: 1 · 2023: 2 · 2022: 8 · 2021: 6
FWCI: 3.83
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Journal of Human Genetics (publishedVersion)
PubMed (publishedVersion)
Funders: Japan Agency for Medical Research and Development (JP20ek0109280, JP20dm0107090, JP20ek0109301, JP20ek0109348)
MEXT | Japan Society for the Promotion of Science (JP17H01539, JP19H03621)
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: exosomes, biallelic variants, motor neuronopathy, cerebellar atrophy, pontine atrophy, intellectual disability, developmental delay, nonsense mutation, frameshift mutation, missense mutations, neurodegenerative diseases
MeSH terms: Atrophy, Cerebellar Diseases, Female, Humans, Infant, Male, Muscular Atrophy, Spinal, Mutation, Olivopontocerebellar Atrophies, Pedigree, Motor Neuron Disease, RNA-Binding Proteins, Genetic Association Studies, Exosome Multienzyme Ribonuclease Complex

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Novel EXOSC9 variants cause pontocerebellar hypoplasia type 1D with spinal motor neuronopathy and cerebellar atrophy

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