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Distinct pathophysiological mechanisms of CEP152 variants in microcephaly and brain abnormalities.

Overview

Authors: Nanako Hamada1, Lama AlAbdi2, Tomoko Uehara3,4, Looprasertkul Sasikarn5,6, Takuma Nishijo1, Reut Suliman-Lavie7, Mais O Hashem2, Majid Alfadhel8,9,10, Shatha Alhefdhi11, Brahim Tabarki12, Malak Alghamdi13, Ikuko Iwamoto1, Toshiki Takenouchi14, Kenjiro Kosaki4, Sagiv Shifman7, Seiji Mizuno3, Nobuhiko Ohno6,15, Fowzan S Alkuraya2,16, Koh-ichi Nagata1,17
ORCID iDs: Nanako Hamada, Tomoko Uehara, Shatha Alhefdhi, Sagiv Shifman, Nobuhiko Ohno, Koh-ichi Nagata
17 affiliations
  1. Department of Molecular Neurobiology, Institute for Developmental Research, Aichi Developmental Disability Center,Kasugai, 480-0392 Japan
  2. Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center,Riyadh, 11211 Saudi Arabia
  3. Central Hospital, Aichi Developmental Disability Center,Kasugai, 480-0392 Japan
  4. Center for Medical Genetics, Keio University Graduate School of Medicine,Tokyo, 160-8582 Japan
  5. Section of Electron Microscopy, Supportive Center for Brain Research, National Institute for Physiological Sciences, National Institutes of Natural Sciences,Okazaki, 444-8787 Japan
  6. Department of Anatomy, Division of Histology and Cell Biology, School of Medicine, Jichi Medical University,Shimotsuke, 329-0498 Japan
  7. Department of Genetics, The Alexander Silberman Institute of Life Sciences The Hebrew University of Jerusalem,Jerusalem, 91904 Israel
  8. Medical Genomics Research Department, King Abdullah International Medical Research Center, King Abdullah Specialized Children’s Hospital, King Abdulaziz Medical City, Ministry of National Guard Health Affairs,Riyadh, Saudi Arabia
  9. King Saud Bin Abdulaziz University for Health Sciences, King Abdullah Specialized Children’s Hospital, King Abdulaziz Medical City, Ministry of National Guard Health Affairs,Riyadh, Saudi Arabia
  10. Genetics and Precision Medicine Department, King Abdullah Specialized Children’s Hospital, King Abdulaziz Medical City, Ministry of National Guard Health Affairs,Riyadh, Saudi Arabia
  11. Medical Genetics Division, Department of Pediatrics, King Khalid University Hospital, King Saud University,Riyadh, 12372 Saudi Arabia
  12. Division of Neurology, Department of Pediatrics, Prince Sultan Military Medical City,Riyadh, Saudi Arabia
  13. Medical Genetics Division, Pediatrics Department, College of Medicine, King Saud University,Riyadh, Saudi Arabia
  14. Department of Pediatrics, Keio University Graduate School of Medicine,Tokyo, 160-8582 Japan
  15. Division of Ultrastructural Research, National Institutes of Natural Sciences,Okazaki, 444-8787 Japan
  16. Lifera Omics, Riyadh, Saudi Arabia
  17. Department of Neurochemistry, Nagoya University Graduate School of Medicine,Nagoya, 466-8550 Japan
Institutions: Aichi Developmental Disability Center (Japan); King Faisal Specialist Hospital & Research Centre (Saudi Arabia); Keio University (Japan); National Institutes of Natural Sciences (Japan); Jichi Medical University (Japan); Hebrew University of Jerusalem (Israel); National Guard Health Affairs (Saudi Arabia); King Saud bin Abdulaziz University for Health Sciences (Saudi Arabia); King Saud University (Saudi Arabia); Riyadh Armed Forces Hospital (Saudi Arabia); Nagoya University (Japan)
Journal: EMBO molecular medicine, volume 18, issue 6, pages 2180-2212
Dates: received 11 May 2025; accepted 30 March 2026; published online 5 May 2026; in print June 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1038/s44321-026-00427-3 · PMID 42086905 · PMCID PMC13270125 · OpenAlex W7160270045
Open access: gold, a free copy (OpenAlex)
Status: data only
Categories: human (organism), mouse (organism), cellular / molecular (subfield)
Methods: Spectral & time-frequency, Statistics, Evoked potentials
Keywords: Genetics, Gene Therapy & Genetic Disease, Neuroscience
MeSH: Brain*, Cell Cycle Proteins*, Centrosomal Associated Proteins*, Microcephaly*, Animals, Centrioles, Centrosome, Female, Humans, Male, Mice (* major topic)
Topic: Microtubule and mitosis dynamics (Cell Biology, Biochemistry, Genetics and Molecular Biology), according to OpenAlex
Funding: Japan Society for the Promotion of Science (JP22H03049, JP20K21589, 23K07284, JP22H04926); Daiko Foundation (大幸財団) (9234); Israel Science Foundation (ISF) (1863/24)
Citations: cited by 1 paper (Europe PMC); 60 references in the paper
Research resources: RRID:CVCL_0224, mouse neuroblastoma cell line N2a RRID:CVCL_0470

Abstract

CEP152 is essential for centriole function and neurodevelopment, and pathogenic recessive variants in CEP152 cause primary microcephaly. We identified new compound heterozygous CEP152 variants, c.314 G > A,p.(W105*) and c.2689 A > T,p.(K897*), in a microcephalic patient and analyzed them alongside a homozygous variant c.95 A > C,p.(Q32P) associated with severe microcephaly with marked gyral simplification. In vitro assays revealed distinct effects: p.K897* prevented centrosomal localization, p.W105* led to protein degradation, and p.Q32P retained centrosomal targeting but disrupted binding to Polo-like kinase 4, a key centriole biogenesis kinase and CEP152 partner. In vivo, both Cep152W105*/K897* and Cep152Q32P/Q32P knock-in mice displayed microcephaly; notably, Cep152Q32P/Q32P mice also exhibited severe cortical defects during brain development. Cellular analyses revealed centrosome dysfunction, mitotic errors, and increased apoptosis, which were exacerbated in Cep152Q32P/Q32P brains. Morphological examination, including electron microscopy, further demonstrated structural abnormalities of the centrosomes and centrioles in Cep152Q32P/Q32P brains. Electrophysiological and gene expression analyses confirmed variant-specific neuronal impairments, which correlate with clinical severity. Collectively, these findings demonstrate that distinct CEP152 variants disrupt neurodevelopment through different mechanisms, thereby explaining the spectrum of microcephaly severity and associated phenotypes.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

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Data

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Data availability

The datasets produced in this study are available in the following databases: RNA-seq: NCBI Gene Expression Omnibus (GEO) GSE325064 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE325064) (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE325064).

The source data of this paper are collected in the following database record: biostudies:S-SCDT-10_1038-S44321-026-00427-3 (https://www.ebi.ac.uk/biostudies/sourcedata/studies/S-SCDT-10_1038-S44321-026-00427-3).

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 28 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 19 authors, 2 keywords, 11 MeSH terms, 3 funders, 60 references, 2 RRIDs.

Cite

This paper

Hamada, N., AlAbdi, L., Uehara, T., Sasikarn, L., Nishijo, T., Suliman-Lavie, R., Hashem, M. O., Alfadhel, M., Alhefdhi, S., Tabarki, B., Alghamdi, M., Iwamoto, I., Takenouchi, T., Kosaki, K., Shifman, S., Mizuno, S., Ohno, N., Alkuraya, F. S., & Nagata, K.-i. (2026). Distinct pathophysiological mechanisms of CEP152 variants in microcephaly and brain abnormalities. EMBO molecular medicine, 18(6), 2180-2212. https://doi.org/10.1038/s44321-026-00427-3

BibTeX

@article{hamada2026distinct,
author = {Hamada, Nanako and AlAbdi, Lama and Uehara, Tomoko and Sasikarn, Looprasertkul and Nishijo, Takuma and Suliman-Lavie, Reut and Hashem, Mais O and Alfadhel, Majid and Alhefdhi, Shatha and Tabarki, Brahim and Alghamdi, Malak and Iwamoto, Ikuko and Takenouchi, Toshiki and Kosaki, Kenjiro and Shifman, Sagiv and Mizuno, Seiji and Ohno, Nobuhiko and Alkuraya, Fowzan S and Nagata, Koh-ichi},
title = {{Distinct pathophysiological mechanisms of CEP152 variants in microcephaly and brain abnormalities}},
journal = {EMBO molecular medicine},
year = {2026},
month = may,
volume = {18},
number = {6},
pages = {2180--2212},
publisher = {Nature Publishing Group},
issn = {1757-4676},
doi = {10.1038/s44321-026-00427-3},
url = {https://doi.org/10.1038/s44321-026-00427-3},
pmid = {42086905},
pmcid = {PMC13270125}
}

RIS

TY - JOUR
AU - Hamada, Nanako
AU - AlAbdi, Lama
AU - Uehara, Tomoko
AU - Sasikarn, Looprasertkul
AU - Nishijo, Takuma
AU - Suliman-Lavie, Reut
AU - Hashem, Mais O
AU - Alfadhel, Majid
AU - Alhefdhi, Shatha
AU - Tabarki, Brahim
AU - Alghamdi, Malak
AU - Iwamoto, Ikuko
AU - Takenouchi, Toshiki
AU - Kosaki, Kenjiro
AU - Shifman, Sagiv
AU - Mizuno, Seiji
AU - Ohno, Nobuhiko
AU - Alkuraya, Fowzan S
AU - Nagata, Koh-ichi
TI - Distinct pathophysiological mechanisms of CEP152 variants in microcephaly and brain abnormalities
T2 - EMBO molecular medicine
J2 - EMBO Mol Med
PY - 2026
DA - 2026/05/05
VL - 18
IS - 6
SP - 2180
EP - 2212
SN - 1757-4676
PB - Nature Publishing Group
DO - 10.1038/s44321-026-00427-3
UR - https://doi.org/10.1038/s44321-026-00427-3
LA - en
ER -

CSL-JSON

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