SPECC1L regulates palate development downstream of IRF6.

Autor:	Hall EG; Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA., Wenger LW; Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA., Wilson NR; Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA., Undurty-Akella SS; Department of Pediatrics, Craniofacial Anomalies Research Center, University of Iowa, Iowa City, IA 52242, USA., Standley J; Department of Pediatrics, Craniofacial Anomalies Research Center, University of Iowa, Iowa City, IA 52242, USA., Augustine-Akpan EA; Department of Oral Pathology, Radiology and Medicine/Dow Institute for Dental Research, College of Dentistry, University of Iowa, Iowa City, IA 52242, USA., Kousa YA; Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA., Acevedo DS; Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA., Goering JP; Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA., Pitstick L; Department of Biochemistry, Midwestern University, Downers Grove, IL 60515, USA., Natsume N; Division of Research and Treatment for Oral and Maxillofacial Congenital Anomalies, Aichi Gakuin University Hospital, 2-11 Suemori-Dori, Nagoya, Chikusa-ku, Japan., Paroya SM; Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA., Busch TD; Department of Pediatrics, Craniofacial Anomalies Research Center, University of Iowa, Iowa City, IA 52242, USA., Ito M; Division of Research and Treatment for Oral and Maxillofacial Congenital Anomalies, Aichi Gakuin University Hospital, 2-11 Suemori-Dori, Nagoya, Chikusa-ku, Japan., Mori A; Division of Research and Treatment for Oral and Maxillofacial Congenital Anomalies, Aichi Gakuin University Hospital, 2-11 Suemori-Dori, Nagoya, Chikusa-ku, Japan., Imura H; Division of Research and Treatment for Oral and Maxillofacial Congenital Anomalies, Aichi Gakuin University Hospital, 2-11 Suemori-Dori, Nagoya, Chikusa-ku, Japan., Schultz-Rogers LE; Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USA., Klee EW; Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USA.; Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USA., Babovic-Vuksanovic D; Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USA., Kroc SA; Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USA., Adeyemo WL; Department of Oral and Maxillofacial Surgery, College of Medicine, University of Lagos, Lagos, PMB 12003, Nigeria., Eshete MA; Department of Plastic and Reconstructive Surgery, Addis Ababa University, Addis Ababa, PO Box 26493, Ethiopia., Bjork BC; Department of Biochemistry, Midwestern University, Downers Grove, IL 60515, USA., Suzuki S; Department of Pediatrics, Craniofacial Anomalies Research Center, University of Iowa, Iowa City, IA 52242, USA.; Division of Research and Treatment for Oral and Maxillofacial Congenital Anomalies, Aichi Gakuin University Hospital, 2-11 Suemori-Dori, Nagoya, Chikusa-ku, Japan., Murray JC; Department of Pediatrics, Craniofacial Anomalies Research Center, University of Iowa, Iowa City, IA 52242, USA., Schutte BC; Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI 48824, USA.; Department of Pediatrics and Human Development, Michigan State University, East Lansing, MI 48824, USA., Butali A; Department of Oral Pathology, Radiology and Medicine/Dow Institute for Dental Research, College of Dentistry, University of Iowa, Iowa City, IA 52242, USA., Saadi I; Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA.
Jazyk:	angličtina
Zdroj:	Human molecular genetics [Hum Mol Genet] 2020 Mar 27; Vol. 29 (5), pp. 845-858.
DOI:	10.1093/hmg/ddaa002
Abstrakt:	SPECC1L mutations have been identified in patients with rare atypical orofacial clefts and with syndromic cleft lip and/or palate (CL/P). These mutations cluster in the second coiled-coil and calponin homology domains of SPECC1L and severely affect the ability of SPECC1L to associate with microtubules. We previously showed that gene-trap knockout of Specc1l in mouse results in early embryonic lethality. We now present a truncation mutant mouse allele, Specc1lΔC510, that results in perinatal lethality. Specc1lΔC510/ΔC510 homozygotes showed abnormal palate rugae but did not show cleft palate. However, when crossed with a gene-trap allele, Specc1lcGT/ΔC510 compound heterozygotes showed a palate elevation delay with incompletely penetrant cleft palate. Specc1lcGT/ΔC510 embryos exhibit transient oral epithelial adhesions at E13.5, which may delay shelf elevation. Consistent with oral adhesions, we show periderm layer abnormalities, including ectopic apical expression of adherens junction markers, similar to Irf6 hypomorphic mutants and Arhgap29 heterozygotes. Indeed, SPECC1L expression is drastically reduced in Irf6 mutant palatal shelves. Finally, we wanted to determine if SPECC1L deficiency also contributed to non-syndromic (ns) CL/P. We sequenced 62 Caucasian, 89 Filipino, 90 Ethiopian, 90 Nigerian and 95 Japanese patients with nsCL/P and identified three rare coding variants (p.Ala86Thr, p.Met91Iso and p.Arg546Gln) in six individuals. These variants reside outside of SPECC1L coiled-coil domains and result in milder functional defects than variants associated with syndromic clefting. Together, our data indicate that palate elevation is sensitive to deficiency of SPECC1L dosage and function and that SPECC1L cytoskeletal protein functions downstream of IRF6 in palatogenesis. (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
Databáze:	MEDLINE
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