Damaging Mutations in AFDN Contribute to Risk of Nonsyndromic Cleft Lip With or Without Cleft Palate
| Title: | Damaging Mutations in AFDN Contribute to Risk of Nonsyndromic Cleft Lip With or Without Cleft Palate |
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| Authors: | Awotoye, Waheed; Mossey, Peter A.; Hetmanski, Jacqueline B.; Gowans, Lord J. J.; Eshete, Mekonen A.; Adeyemo, Wasiu L.; Alade, Azeez; Zeng, Erliang; Adamson, Olawale; James, Olutayo; Fashina, Azeez; Ogunlewe, Modupe O.; Naicker, Thirona; Adeleke, Chinyere; Busch, Tamara; Li, Mary; Petrin, Aline; Oladayo, Abimbola; Kayali, Sami; Olotu, Joy; Sule, Veronica; Hassan, Mohaned; Pape, John; Aladenika, Emmanuel T.; Donkor, Peter; Arthur, Fareed K. N.; Obiri-Yeboah, Solomon; Sabbah, Daniel K.; Agbenorku, Pius; Ray, Debashree; Plange-Rhule, Gyikua; Oti, Alexander Acheampong; Albokhari, Daniah; Sobreira, Nara; Dunnwald, Martine; Beaty, Terri H.; Taub, Margaret; Marazita, Mary L.; Adeyemo, Adebowale A.; Murray, Jeffrey C.; Butali, Azeez |
| Source: | Awotoye, W, Mossey, P A, Hetmanski, J B, Gowans, L J J, Eshete, M A, Adeyemo, W L, Alade, A, Zeng, E, Adamson, O, James, O, Fashina, A, Ogunlewe, M O, Naicker, T, Adeleke, C, Busch, T, Li, M, Petrin, A, Oladayo, A, Kayali, S, Olotu, J, Sule, V, Hassan, M, Pape, J, Aladenika, E T, Donkor, P, Arthur, F K N, Obiri-Yeboah, S, Sabbah, D K, Agbenorku, P, Ray, D, Plange-Rhule, G, Oti, A A, Albokhari, D, Sobreira, N, Dunnwald, M, Beaty, T H, Taub, M, Marazita, M L, Adeyemo, A A, Murray, J C & Butali, A .... |
| Publication Year: | 2024 |
| Collection: | Discovery - University of Dundee Online Publications |
| Subject Terms: | AFDN; cell adhesion molecule; cleft; craniofacial genetics; damaging mutations; next-generation sequencing; pathogenic variants; thermodynamics; /dk/atira/pure/subjectarea/asjc/3500/3504; name=Oral Surgery; /dk/atira/pure/subjectarea/asjc/2700/2733; name=Otorhinolaryngology |
| Description: | Objectives : Novel or rare damaging mutations have been implicated in the developmental pathogenesis of nonsyndromic cleft lip with or without cleft palate (nsCL ± P). Thus, we investigated the human genome for high-impact mutations that could explain the risk of nsCL ± P in our cohorts. Materials and Methods : We conducted next-generation sequencing (NGS) analysis of 130 nsCL ± P case-parent African trios to identify pathogenic variants that contribute to the risk of clefting. We replicated this analysis using whole-exome sequence data from a Brazilian nsCL ± P cohort. Computational analyses were then used to predict the mechanism by which these variants could result in increased risks for nsCL ± P. Results : We discovered damaging mutations within the AFDN gene, a cell adhesion molecule (CAMs) that was previously shown to contribute to cleft palate in mice. These mutations include p.Met1164Ile, p.Thr453Asn, p.Pro1638Ala, p.Arg669Gln, p.Ala1717Val, and p.Arg1596His. We also discovered a novel splicing p.Leu1588Leu mutation in this protein. Computational analysis suggests that these amino acid changes affect the interactions with other cleft-associated genes including nectins (PVRL1, PVRL2, PVRL3, and PVRL4) CDH1, CTNNA1, and CTNND1. Conclusion : This is the first report on the contribution of AFDN to the risk for nsCL ± P in humans. AFDN encodes AFADIN, an important CAM that forms calcium-independent complexes with nectins 1 and 4 (encoded by the genes PVRL1 and PVRL4). This discovery shows the power of NGS analysis of multiethnic cleft samples in combination with a computational approach in the understanding of the pathogenesis of nsCL ± P. |
| Document Type: | article in journal/newspaper |
| File Description: | application/pdf |
| Language: | English |
| ISSN: | 1055-6656; 1545-1569 |
| Relation: | info:eu-repo/semantics/altIdentifier/pmid/36384317; info:eu-repo/semantics/altIdentifier/pissn/1055-6656; info:eu-repo/semantics/altIdentifier/eissn/1545-1569 |
| DOI: | 10.1177/10556656221135926 |
| Availability: | https://discovery.dundee.ac.uk/en/publications/7f01798a-be17-4b45-8010-bffaa693026b; https://doi.org/10.1177/10556656221135926; https://discovery.dundee.ac.uk/ws/files/92822729/Damaging_mutations_in_Afadin_contribute_to_risk_of_nsCL_P_updated_1_Final_Revised.pdf; https://discovery.dundee.ac.uk/ws/files/92822731/Supplementary_file.pdf; https://discovery.dundee.ac.uk/ws/files/92822733/Figures_for_Afadin_discovery_prep.for_submission_.pdf; https://www.scopus.com/pages/publications/85142305070 |
| Rights: | info:eu-repo/semantics/openAccess |
| Accession Number: | edsbas.F9A8769D |
| Database: | BASE |