Pathogenic variants in the paired-related homeobox 1 gene (PRRX1) cause craniosynostosis with incomplete penetrance

Tooze, Rebecca S.; Miller, Kerry A.; Swagemakers, Sigrid; Calpena, Eduardo; McGowan, Simon J.; Boute, Odile; Collet, Corinne; Johnson, David H.; Laffargue, Fanny; Leeuw, Nicole de; Morton, Jenny V.; Noons, Peter; Ockeloen, Charlotte W.; Phipps, Julie; Tan, Tiong Yang; Timberlake, Andrew T.; Vanlerberghe, Clémence; Wall, Steven A.; Weber, Astrid; Wilson, Louise C.; Zackai, Elaine H.; Mathijssen, Irene M.J.; Twigg, Stephen R.F.

doi:10.1016/j.gim.2023.100883

Cited by 5 publications

(3 citation statements)

References 44 publications

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“…While more than 50 genes have been implicated in craniosynostosis (Twigg & Wilkie, 2015), instances of incomplete penetrance have been occasionally noted, particularly in haploinsufficient genes in the cases of ERF, TCF12, and SMAD6 genes. Recently, a novel genetic association between craniosynostosis and the paired-related homeobox 1 gene (PRRX1) was reported with incomplete penetrance (Tooze et al, 2023). This study underscores PRRX1 haploinsufficiency as a likely pathogenic mechanism of craniosynostosis, drawing attention to a relatively high prevalence of rare deleterious PRRX1 variants detected in 17 cases and 14 unrelated families with craniosynostosis.…”

mentioning

confidence: 74%

Multi‐locus pathogenic variation identified in a patient with craniosynostosis

Yoon,

Yu,

Shim

et al. 2023

American J of Med Genetics Pt A

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mentioning

confidence: 74%

Multi‐locus pathogenic variation identified in a patient with craniosynostosis

Yoon,

Yu,

Shim

et al. 2023

American J of Med Genetics Pt A

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“…However, several of the genes in this list of disease-enriched have well-described roles in spatial patterning [e.g., GAL ( 91 ), WNT10A ( 92 ), TLL1 ( 93 ), for example]. Others have been directly implicated in congenital malformations associated with cognitive impairment [e.g., PRRX1 ( 94 ), NR2F2 ( 95 ), MGAT5 ( 96 )]. In most of these latter cases, direct links between the phenotype and neurodevelopmental patterning have not yet been investigated, but one recent study showed MGAT5 knockout resulted in a spatial shift of cortical neuron layers ( 97 ).…”

Section: Discussionmentioning

confidence: 99%

Deciphering the functional specialization of whole-brain spatiomolecular gradients in the adult brain

Vogel,

Alexander-Bloch,

Wagstyl

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

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Cortical arealization arises during neurodevelopment from the confluence of molecular gradients representing patterned expression of morphogens and transcription factors. However, whether similar gradients are maintained in the adult brain remains unknown. Here, we uncover three axes of topographic variation in gene expression in the adult human brain that specifically capture previously identified rostral-caudal, dorsal-ventral, and medial-lateral axes of early developmental patterning. The interaction of these spatiomolecular gradients i) accurately reconstructs the position of brain tissue samples, ii) delineates known functional territories, and iii) can model the topographical variation of diverse cortical features. The spatiomolecular gradients are distinct from canonical cortical axes differentiating the primary sensory cortex from the association cortex, but radiate in parallel with the axes traversed by local field potentials along the cortex. We replicate all three molecular gradients in three independent human datasets as well as two nonhuman primate datasets and find that each gradient shows a distinct developmental trajectory across the lifespan. The gradients are composed of several well-known transcription factors (e.g., PAX6 and SIX3 ), and a small set of genes shared across gradients are strongly enriched for multiple diseases. Together, these results provide insight into the developmental sculpting of functionally distinct brain regions, governed by three robust transcriptomic axes embedded within brain parenchyma.

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“…Tooze identified a significant enrichment of rare Prrx1 gene variants or deletions in patients with craniosynostosis or premature cranial suture closure, often with severe symptoms ( Tooze et al, 2023 ). A follow-up of these patients’ families revealed that Prrx1 gene variants are heritable, highlighting the importance of regular examinations and monitoring of cranial bone status in individuals with pathogenic Prrx1 mutations and their families.…”

Section: Suture Mesenchymal Stem Cellsmentioning

confidence: 99%

Mesenchymal stem cells in craniofacial reconstruction: a comprehensive review

Zheng,

Liu,

Liu

et al. 2024

Front. Mol. Biosci.

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Craniofacial reconstruction faces many challenges, including high complexity, strong specificity, severe injury, irregular and complex wounds, and high risk of bleeding. Traditionally, the “gold standard” for treating craniofacial bone defects has been tissue transplantation, which involves the transplantation of bone, cartilage, skin, and other tissues from other parts of the body. However, the shape of craniofacial bone and cartilage structures varies greatly and is distinctly different from ordinary long bones. Craniofacial bones originate from the neural crest, while long bones originate from the mesoderm. These factors contribute to the poor effectiveness of tissue transplantation in repairing craniofacial defects. Autologous mesenchymal stem cell transplantation exhibits excellent pluripotency, low immunogenicity, and minimally invasive properties, and is considered a potential alternative to tissue transplantation for treating craniofacial defects. Researchers have found that both craniofacial-specific mesenchymal stem cells and mesenchymal stem cells from other parts of the body have significant effects on the restoration and reconstruction of craniofacial bones, cartilage, wounds, and adipose tissue. In addition, the continuous development and application of tissue engineering technology provide new ideas for craniofacial repair. With the continuous exploration of mesenchymal stem cells by researchers and the continuous development of tissue engineering technology, the use of autologous mesenchymal stem cell transplantation for craniofacial reconstruction has gradually been accepted and promoted. This article will review the applications of various types of mesenchymal stem cells and related tissue engineering in craniofacial repair and reconstruction.

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Pathogenic variants in the paired-related homeobox 1 gene (PRRX1) cause craniosynostosis with incomplete penetrance

Cited by 5 publications

References 44 publications

Multi‐locus pathogenic variation identified in a patient with craniosynostosis

Multi‐locus pathogenic variation identified in a patient with craniosynostosis

Deciphering the functional specialization of whole-brain spatiomolecular gradients in the adult brain

Mesenchymal stem cells in craniofacial reconstruction: a comprehensive review

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