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SPECC1L regulates palate development downstream of IRF6.

Authors:
Everett G Hall Luke W Wenger Nathan R Wilson Sraavya S Undurty-Akella Jennifer Standley Eno-Abasi Augustine-Akpan Youssef A Kousa Diana S Acevedo Jeremy P Goering Lenore Pitstick Nagato Natsume Shahnawaz M Paroya Tamara D Busch Masaaki Ito Akihiro Mori Hideto Imura Laura E Schultz-Rogers Eric W Klee Dusica Babovic-Vuksanovic Sarah A Kroc Wasiu L Adeyemo Mekonen A Eshete Bryan C Bjork Satoshi Suzuki Jeffrey C Murray Brian C Schutte Azeez Butali Irfan Saadi

Hum Mol Genet 2020 03;29(5):845-858

Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA.

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.

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http://dx.doi.org/10.1093/hmg/ddaa002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7104672PMC
March 2020

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