Summary: Researchers have linked a mutation in the BCL11B gene to a rare skull development disorder called craniosynostosis.
Source: Oregon State University
Overview
Scientists from Oregon State University, the University of Oxford and Erasmus University have identified a previously unreported genetic mutation that causes premature fusion of the skull’s bony plates, a condition known as craniosynostosis. This discovery advances understanding of how BCL11B functions in skull development and may shed light on its roles in other tissues, including skin, teeth and the immune system.
About craniosynostosis
Craniosynostosis occurs when one or more cranial sutures — the fibrous joints between the bones of the skull — close too early. The premature ossification interferes with normal skull and brain growth and can raise intracranial pressure, which in turn may cause vision problems, breathing difficulties, cognitive issues and abnormal head shape. The disorder affects roughly one in 2,250 children; males are affected at slightly higher rates, and most cases are classified as sporadic, meaning they arise without a family history.
During normal development, sutures remain open through childhood and only complete fusion typically occurs in the third decade of life. Proper suture formation and maintenance require tightly regulated timing of stem cell proliferation and differentiation so that bone growth and closure occur in balance.
Discovery and genetic findings
Using whole-genome sequencing, researchers analyzed DNA from a male patient who presented with coronal suture synostosis and identified a de novo mutation in the BCL11B gene. The change, described as c.7C>A and resulting in an R3S amino acid substitution (p.R3S), was not present in the patient’s parents and there was no family history of craniosynostosis. BCL11B encodes a transcription factor known to interact with chromatin-remodeling complexes involved in gene regulation.
Biochemical and computational analyses indicate that the p.R3S substitution lies within a conserved amino-terminal motif of BCL11B and weakens the protein’s interaction with essential transcriptional complexes, including subunits of the nucleosome remodeling and deacetylation (NuRD) complex. Molecular dynamics simulations and binding studies showed that the substitution disrupts ionic interactions and increases flexibility in nearby residues, collectively reducing the affinity of BCL11B for its molecular partners by nearly an order of magnitude.
Mouse model confirms causality
To test whether the BCL11B variant is causative for craniosynostosis, the team generated a mouse model carrying the same p.R3S substitution using CRISPR-Cas9 genome editing. The engineered mice displayed craniosynostosis of the coronal suture and other cranial sutures at birth, mirroring the human patient’s condition and providing strong evidence that this BCL11B alteration directly leads to suture closure defects.
According to Mark Leid, professor and interim dean of the OSU College of Pharmacy, the mouse model will be a valuable tool for dissecting the mechanisms by which BCL11B maintains suture patency and for exploring how the protein influences development and function in other organ systems.
Research team
The collaborative effort included Mark Leid, Theresa Filtz, Walter Vogel, and graduate students Elahe Esfandiari, Wisam Hussein Selman and Evan Carpenter at Oregon State College of Pharmacy; Urszula Iwaniec at the OSU College of Public Health and Human Sciences; and investigators from the University of Oxford, Erasmus University Rotterdam and the University of Leicester. The multidisciplinary team combined genomics, structural biology, molecular assays and in vivo modeling to reach these conclusions.
Source:
Oregon State University
Media Contacts:
Mark Leid – Oregon State University
Image Source:
The image is in the public domain.
Original research (open access):
“A de novo substitution in BCL11B leads to loss of interaction with transcriptional complexes and craniosynostosis.” Mark Leid et al., Human Molecular Genetics. doi: 10.1093/hmg/ddz072
Abstract (summary)
Researchers report a novel, de novo BCL11B variant (c.7C>A; p.R3S) identified by whole-genome sequencing in a male patient with coronal suture synostosis. Functional and structural studies reveal that this substitution reduces BCL11B’s interaction with chromatin-regulating complexes, altering binding affinity and conformational dynamics. A CRISPR-Cas9 mouse model carrying the same substitution developed coronal and additional cranial suture synostosis, providing experimental evidence that the BCL11B p.R3S variant is causally associated with craniosynostosis and confirming BCL11B’s role in maintaining cranial suture patency.
