Journal article
SPECC1L regulates palate development downstream of IRF6
Human molecular genetics, Vol.29(5), pp.845-858
01/29/2020
DOI: 10.1093/hmg/ddaa002
PMCID: PMC7104672
PMID: 31943082
Abstract
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.
Details
- Title: Subtitle
- SPECC1L regulates palate development downstream of IRF6
- Creators
- Everett G Hall - University of Kansas Medical CenterLuke W Wenger - University of Kansas Medical CenterJeffrey C Murray - University of IowaNathan R Wilson - University of Kansas Medical CenterAzeez Butali - University of IowaSraavya S Undurty-Akella - University of IowaJennifer Standley - University of IowaEno-Abasi Augustine-Akpan - University of IowaYoussef A Kousa - Michigan State UniversityDiana S Acevedo - University of Kansas Medical CenterJeremy P Goering - University of Kansas Medical CenterLenore Pitstick - Midwestern UniversityNagato Natsume - Aichi Gakuin UniversityShahnawaz M Paroya - University of Kansas Medical CenterTamara D Busch - University of IowaMasaaki Ito - Aichi Gakuin UniversityAkihiro Mori - Aichi Gakuin UniversityDusica Babovic-Vuksanovic - Department of Clinical Genomics Mayo Clinic, Rochester, MN, 55905 USAHideto Imura - Aichi Gakuin UniversitySarah A Kroc - Department of Clinical Genomics Mayo Clinic, Rochester, MN, 55905 USALaura E Schultz-Rogers - Mayo ClinicEric W Klee - Mayo ClinicWasiu L Adeyemo - University of LagosMekonen A Eshete - Addis Ababa UniversityBryan C Bjork - Midwestern UniversitySatoshi Suzuki - University of IowaBrian C Schutte - Michigan State UniversityIrfan Saadi - University of Kansas Medical Center
- Resource Type
- Journal article
- Publication Details
- Human molecular genetics, Vol.29(5), pp.845-858
- DOI
- 10.1093/hmg/ddaa002
- PMID
- 31943082
- PMCID
- PMC7104672
- NLM abbreviation
- Hum Mol Genet
- ISSN
- 0964-6906
- eISSN
- 1460-2083
- Publisher
- Oxford University Press
- Grant note
- DE026172; DE022378; GM102801; F31DE027284 / ; ; HD 090216 / ; ; U54HD090216 / ; ; JP24249092; JP26861757; JP17K11863 / ; ; 72429 / ; ; ; ; P30GM122731 / ; ; P20 GM104936; P20 GM103418 / ; ;
- Language
- English
- Date published
- 01/29/2020
- Academic Unit
- Oral Pathology, Radiology and Medicine; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Epidemiology; Pediatric Dentistry; Craniofacial Anomalies Research Center; Dental Research
- Record Identifier
- 9984353843502771
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