Bi-allelic variants in CEP295 cause Seckel-like syndrome presenting with primary microcephaly, developmental delay, intellectual disability, short stature, craniofacial and digital abnormalities.

Bi-allelic variants of CEP295 Centriole and centrosome development Ciliogenesis Primary microcephaly Seckel-like syndrome

Journal

EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039

Informations de publication

Date de publication:
27 Dec 2023
Historique:
received: 09 12 2022
revised: 13 12 2023
accepted: 13 12 2023
medline: 29 12 2023
pubmed: 29 12 2023
entrez: 28 12 2023
Statut: aheadofprint

Résumé

Pathogenic variants in the centrosome protein (CEP) family have been implicated in primary microcephaly, Seckel syndrome, and classical ciliopathies. However, most CEP genes remain unlinked to specific Mendelian genetic diseases in humans. We sought to explore the roles of CEP295 in human pathology. Whole-exome sequencing was performed to screen for pathogenic variants in patients with severe microcephaly. Patient-derived fibroblasts and CEP295-depleted U2OS and RPE1 cells were used to clarify the underlying pathomechanisms, including centriole/centrosome development, cell cycle and proliferation changes, and ciliogenesis. Complementary experiments using CEP295 mRNA were performed to determine the pathogenicity of the identified missense variant. Here, we report bi-allelic variants of CEP295 in four children from two unrelated families, characterized by severe primary microcephaly, short stature, developmental delay, intellectual disability, facial deformities, and abnormalities of fingers and toes, suggesting a Seckel-like syndrome. Mechanistically, depletion of CEP295 resulted in a decrease in the numbers of centrioles and centrosomes and triggered p53-dependent G This study reports CEP295 as a causative gene of the syndromic microcephaly phenotype in humans. Our study also demonstrates that defects in CEP295 result in primary ciliary defects. A full list of funding bodies that contributed to this study can be found under "Acknowledgments."

Sections du résumé

BACKGROUND BACKGROUND
Pathogenic variants in the centrosome protein (CEP) family have been implicated in primary microcephaly, Seckel syndrome, and classical ciliopathies. However, most CEP genes remain unlinked to specific Mendelian genetic diseases in humans. We sought to explore the roles of CEP295 in human pathology.
METHODS METHODS
Whole-exome sequencing was performed to screen for pathogenic variants in patients with severe microcephaly. Patient-derived fibroblasts and CEP295-depleted U2OS and RPE1 cells were used to clarify the underlying pathomechanisms, including centriole/centrosome development, cell cycle and proliferation changes, and ciliogenesis. Complementary experiments using CEP295 mRNA were performed to determine the pathogenicity of the identified missense variant.
FINDINGS RESULTS
Here, we report bi-allelic variants of CEP295 in four children from two unrelated families, characterized by severe primary microcephaly, short stature, developmental delay, intellectual disability, facial deformities, and abnormalities of fingers and toes, suggesting a Seckel-like syndrome. Mechanistically, depletion of CEP295 resulted in a decrease in the numbers of centrioles and centrosomes and triggered p53-dependent G
INTERPRETATION CONCLUSIONS
This study reports CEP295 as a causative gene of the syndromic microcephaly phenotype in humans. Our study also demonstrates that defects in CEP295 result in primary ciliary defects.
FUNDING BACKGROUND
A full list of funding bodies that contributed to this study can be found under "Acknowledgments."

Identifiants

DOI: 10.1016/j.ebiom.2023.104940 PMID: 38154379
pubmed: 38154379
pii: S2352-3964(23)00506-6
doi: 10.1016/j.ebiom.2023.104940
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

104940

Informations de copyright

Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests The authors declare no competing interests.

Auteurs

Niu Li (N)

Department of Reproductive Genetics, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China; Shanghai Key Laboratory of Embryo Original Diseases, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China; Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China; Faculty of Medical Laboratory Science, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.

Yufei Xu (Y)

Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.

Hongzhu Chen (H)

Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.

Jingqi Lin (J)

Shanghai Key Laboratory of Embryo Original Diseases, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.

Lama AlAbdi (L)

Department of Zoology, College of Science, King Saud University, Riyadh, 11533, Saudi Arabia.

Mir Reza Bekheirnia (MR)

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA; Texas Children's Hospital, Houston, TX, 77030, USA; Renal Section, Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA.

Guoqiang Li (G)

Department of Reproductive Genetics, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China; Shanghai Key Laboratory of Embryo Original Diseases, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.

Yoel Gofin (Y)

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA; Texas Children's Hospital, Houston, TX, 77030, USA.

Nasim Bekheirnia (N)

Texas Children's Hospital, Houston, TX, 77030, USA; Renal Section, Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA.

Eissa Faqeih (E)

Department of Pediatric Subspecialties, Children's Hospital, King Fahad Medical City, Riyadh, 11533, Saudi Arabia.

Lina Chen (L)

Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.

Guoying Chang (G)

Department of Endocrinology and Metabolism, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.

Jie Tang (J)

Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.

Ruen Yao (R)

Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China; Faculty of Medical Laboratory Science, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.

Tingting Yu (T)

Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China; Faculty of Medical Laboratory Science, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.

Xiumin Wang (X)

Department of Endocrinology and Metabolism, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.

Wei Fu (W)

Institute of Pediatric Translational Medicine, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.

Qihua Fu (Q)

Institute of Pediatric Translational Medicine, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China; Shanghai Key Laboratory of Clinical Molecular Diagnostics for Pediatrics, Shanghai, 200127, China.

Yiping Shen (Y)

Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.

Fowzan S Alkuraya (FS)

Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, 11211, Saudi Arabia.

Keren Machol (K)

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA; Texas Children's Hospital, Houston, TX, 77030, USA. Electronic address: Keren.Machol@bcm.edu.

Jian Wang (J)

Shanghai Key Laboratory of Embryo Original Diseases, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China; Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China; Faculty of Medical Laboratory Science, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; Shanghai Key Laboratory of Clinical Molecular Diagnostics for Pediatrics, Shanghai, 200127, China. Electronic address: Labwangjian@shsmu.edu.cn.

Classifications MeSH