Splicing Defects and Cell Death Cause <i>SF3B2</i> -Linked Craniofacial Microsomia

Craniofacial microsomia (CFM) is a genetically and phenotypically heterogeneous disorder characterized by hypoplasia of facial tissue that is often asymmetric. Affected tissues typically include the ears (external and internal), mandible, and maxilla, but various extracranial anomalies have also been reported. Loss-of-function variants in the <i>SF3B2</i> gene have recently been reported in 8 cases of CFM, representing one of the more common genetic causes identified to date. To better define the full phenotypic spectrum associated with variants in <i>SF3B2</i>, we report novel loss-of-function variants in <i>SF3B2</i> in 5 new families with CFM. Furthermore, to determine the mechanism by which <i>SF3B2</i> loss-of-function perturbs craniofacial development, we established <i>sf3b2</i>-null mutant zebrafish, which exhibited severe deficiencies in craniofacial cartilage and bone progenitors due to elevated apoptosis and reduced proliferation of cranial neural crest cells. In addition, we generated a heterozygous truncating variant of <i>SF3B2</i> in human induced pluripotent stem cells using CRISPR/Cas9 gene editing. Differentiation of these cells into neural crest cells was accompanied by increased cell death and reduced proliferation. RNA sequencing of <i>sf3b2</i> mutant zebrafish revealed widespread disruption of mRNA splicing, including <i>mdm2</i>, a key regulator of Tp53-mediated apoptosis. Genetic inhibition of <i>tp53</i> in <i>sf3b2</i> mutants demonstrated that <i>tp53</i> inhibition reduces early cell death but does not improve proliferation or craniofacial cartilage development. Therefore, our functional studies indicate that widespread mRNA splicing disruption, in addition to Tp53-dependent cell death, contributes to the craniofacial features observed in <i>SF3B2</i>-related CFM.

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Journal
Journal of Dental Research
Published
2025-04-24
DOI
https://doi.org/10.1177/00220345251325818
Primary Topic
RNA modifications and cancer
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article
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article

Splicing Defects and Cell Death Cause SF3B2 -Linked Craniofacial Microsomia

M.J. Lamb, Lorena Maili, Paul A. Trainor, J. Benjamin Miller et al.
Journal of Dental Research
RNA modifications and cancer
article

Splicing Defects and Cell Death Cause SF3B2 -Linked Craniofacial Microsomia

M.J. Lamb, Lorena Maili, Paul A. Trainor, J. Benjamin Miller, Lisa Gallacher, Matthew D. Gibson, Liza L. Cox, Soma Dash, Tiong Yang Tan, Hamad ul Hassan, Shuyun Rao, Kyle Weaver, Emily Farrow, Timothy C. Cox, Sarina G. Kant, Elizabeth Bhoj, Dongliang Li, Jian Zhang, Yuanwei Zhang, Huili Zhu, Tomi Pastinen, Kristin E.N. Watt
article en

Abstract

Craniofacial microsomia (CFM) is a genetically and phenotypically heterogeneous disorder characterized by hypoplasia of facial tissue that is often asymmetric. Affected tissues typically include the ears (external and internal), mandible, and maxilla, but various extracranial anomalies have also been reported. Loss-of-function variants in the <i>SF3B2</i> gene have recently been reported in 8 cases of CFM, representing one of the more common genetic causes identified to date. To better define the full phenotypic spectrum associated with variants in <i>SF3B2</i>, we report novel loss-of-function variants in <i>SF3B2</i> in 5 new families with CFM. Furthermore, to determine the mechanism by which <i>SF3B2</i> loss-of-function perturbs craniofacial development, we established <i>sf3b2</i>-null mutant zebrafish, which exhibited severe deficiencies in craniofacial cartilage and bone progenitors due to elevated apoptosis and reduced proliferation of cranial neural crest cells. In addition, we generated a heterozygous truncating variant of <i>SF3B2</i> in human induced pluripotent stem cells using CRISPR/Cas9 gene editing. Differentiation of these cells into neural crest cells was accompanied by increased cell death and reduced proliferation. RNA sequencing of <i>sf3b2</i> mutant zebrafish revealed widespread disruption of mRNA splicing, including <i>mdm2</i>, a key regulator of Tp53-mediated apoptosis. Genetic inhibition of <i>tp53</i> in <i>sf3b2</i> mutants demonstrated that <i>tp53</i> inhibition reduces early cell death but does not improve proliferation or craniofacial cartilage development. Therefore, our functional studies indicate that widespread mRNA splicing disruption, in addition to Tp53-dependent cell death, contributes to the craniofacial features observed in <i>SF3B2</i>-related CFM.

Journal of Dental ResearchVol. 104(10)
Stowers Institute for Medical Research (US), Children's Mercy Hospital (US), Children's Hospital of Philadelphia (US), The University of Melbourne (AU), Chinese Academy of Medical Sciences & Peking Union Medical College (CN), Erasmus MC (NL), University at Albany, State University of New York (US), Victorian Clinical Genetics Services (AU), University of Kansas Medical Center (US), Murdoch Children's Research Institute (AU), University of Colorado Anschutz Medical Campus (US), University of Missouri–Kansas City (US), Beihang University (CN), Ministry of Industry and Information Technology (CN)
Children's Hospital of Philadelphia, Stowers Institute for Medical Research, Children's Mercy Hospital, Children’s Hospital of Wisconsin Research Institute, Murdoch Children's Research Institute, Royal Children's Hospital Foundation, American Association for Anatomy, National Natural Science Foundation of China, State Government of Victoria, Erasmus Universitair Medisch Centrum Rotterdam, National Institute of Dental and Craniofacial Research
Good health and well-being
Openalex Percentile: Top 92%
RNA modifications and cancer
DOIOpen Access PDFOpenAlex
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