De novo mutations in the BMP signaling pathway in lambdoid craniosynostosis.

Autor: Timberlake AT; Hansjörg Wyss Department of Plastic Surgery, New York University Langone Medical Center, New York, NY, USA. andrew.timberlake@nyumc.org., Kiziltug E; Department of Genetics, Yale University School of Medicine, New Haven, CT, USA., Jin SC; Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.; Department of Genetics, Washington University School of Medicine, St Louis, MO, USA., Nelson-Williams C; Department of Genetics, Yale University School of Medicine, New Haven, CT, USA., Loring E; Department of Genetics, Yale University School of Medicine, New Haven, CT, USA., Allocco A; Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA., Marlier A; Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA., Banka S; Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9WL, UK.; Manchester Centre for Genomic Medicine, Health Innovation Manchester, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester, M13 9WL, UK., Stuart H; Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9WL, UK.; Manchester Centre for Genomic Medicine, Health Innovation Manchester, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester, M13 9WL, UK., Passos-Buenos MR; Centro de Estudos Do Genoma Humano, Universidade de São Paulo, São Paulo, Brazil., Rosa R; Clinical Genetics, UFCSPA and Irmandade da Santa Casa de Misericórdia de Porto Alegre (ISCMPA), Porto Alegre, RS, Brazil., Rogatto SR; Neogene Laboratory, Research Center (CIPE), AC Camargo Cancer Center, São Paulo, SP, Brazil., Tonne E; Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.; University of Oslo, Oslo, Norway., Stiegler AL; Department of Pharmacology, Yale University, New Haven, CT, USA., Boggon TJ; Department of Pharmacology, Yale University, New Haven, CT, USA., Alperovich M; Section of Plastic and Reconstructive Surgery, Yale University School of Medicine, New Haven, CT, USA., Steinbacher D; Section of Plastic and Reconstructive Surgery, Yale University School of Medicine, New Haven, CT, USA., Staffenberg DA; Hansjörg Wyss Department of Plastic Surgery, New York University Langone Medical Center, New York, NY, USA., Flores RL; Hansjörg Wyss Department of Plastic Surgery, New York University Langone Medical Center, New York, NY, USA., Persing JA; Section of Plastic and Reconstructive Surgery, Yale University School of Medicine, New Haven, CT, USA., Kahle KT; Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.; Broad Institute of Harvard and Massachusetts Institute of Technology, Boston, MA, USA.; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA., Lifton RP; Department of Genetics, Yale University School of Medicine, New Haven, CT, USA. rickl@rockefeller.edu.; Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY, USA. rickl@rockefeller.edu.
Jazyk: angličtina
Zdroj: Human genetics [Hum Genet] 2023 Jan; Vol. 142 (1), pp. 21-32. Date of Electronic Publication: 2022 Aug 23.
DOI: 10.1007/s00439-022-02477-2
Abstrakt: Lambdoid craniosynostosis (CS) is a congenital anomaly resulting from premature fusion of the cranial suture between the parietal and occipital bones. Predominantly sporadic, it is the rarest form of CS and its genetic etiology is largely unexplored. Exome sequencing of 25 kindreds, including 18 parent-offspring trios with sporadic lambdoid CS, revealed a marked excess of damaging (predominantly missense) de novo mutations that account for ~ 40% of sporadic cases. These mutations clustered in the BMP signaling cascade (P = 1.6 × 10 -7 ), including mutations in genes encoding BMP receptors (ACVRL1 and ACVR2A), transcription factors (SOX11, FOXO1) and a transcriptional co-repressor (IFRD1), none of which have been implicated in other forms of CS. These missense mutations are at residues critical for substrate or target sequence recognition and many are inferred to cause genetic gain-of-function. Additionally, mutations in transcription factor NFIX were implicated in syndromic craniosynostosis affecting diverse sutures. Single cell RNA sequencing analysis of the mouse lambdoid suture identified enrichment of mutations in osteoblast precursors (P = 1.6 × 10 -6 ), implicating perturbations in the balance between proliferation and differentiation of osteoprogenitor cells in lambdoid CS. The results contribute to the growing knowledge of the genetics of CS, have implications for genetic counseling, and further elucidate the molecular etiology of premature suture fusion.
(© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
Databáze: MEDLINE
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