Meta-analysis Reveals Genome-Wide Significance at 15q13 for Nonsyndromic Clefting of Both the Lip and the Palate, and Functional Analyses Implicate GREM1 As a Plausible Causative Gene

Ludwig, Kerstin U. y Ahmed, Syeda Tasnim y Böhmer, Anne C. y Sangani, Nasim Bahram y Varghese, Sheryil y Klamt, Johanna y Schuenke, Hannah y Gültepe, Pinar y Hofmann, Andrea y Rubini, Michele y Aldhorae, Khalid Ahmed y Steegers Theunissen, Regine P. y Rojas Martínez, Augusto y Reiter, Rudolf y Borck, Guntram y Knapp, Michael y Nakatomi, Mitsushiro y Graf, Daniel y Mangold, Elisabeth y Peters, Heiko (2016) Meta-analysis Reveals Genome-Wide Significance at 15q13 for Nonsyndromic Clefting of Both the Lip and the Palate, and Functional Analyses Implicate GREM1 As a Plausible Causative Gene. PLoS Genetics, 12 (3). e1005914. ISSN 1553-7404

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Resumen

Nonsyndromic orofacial clefts are common birth defects with multifactorial etiology. The most common type is cleft lip, which occurs with or without cleft palate (nsCLP and nsCLO, respectively). Although genetic components play an important role in nsCLP, the genetic factors that predispose to palate involvement are largely unknown. In this study, we carried out a meta-analysis on genetic and clinical data from three large cohorts and identified strong association between a region on chromosome 15q13 and nsCLP (P = 8.13×10−14 for rs1258763; relative risk (RR): 1.46, 95% confidence interval (CI): 1.32–1.61)) but not nsCLO (P = 0.27; RR: 1.09 (0.94–1.27)). The 5 kb region of strongest association maps downstream of Gremlin-1 (GREM1), which encodes a secreted antagonist of the BMP4 pathway. We show during mouse embryogenesis, Grem1 is expressed in the developing lip and soft palate but not in the hard palate. This is consistent with genotype-phenotype correlations between rs1258763 and a specific nsCLP subphenotype, since a more than two-fold increase in risk was observed in patients displaying clefts of both the lip and soft palate but who had an intact hard palate (RR: 3.76, CI: 1.47–9.61, Pdiff<0.05). While we did not find lip or palate defects in Grem1-deficient mice, wild type embryonic palatal shelves developed divergent shapes when cultured in the presence of ectopic Grem1 protein (P = 0.0014). The present study identified a non-coding region at 15q13 as the second, genome-wide significant locus specific for nsCLP, after 13q31. Moreover, our data suggest that the closely located GREM1 gene contributes to a rare clinical nsCLP entity. This entity specifically involves abnormalities of the lip and soft palate, which develop at different time-points and in separate anatomical regions.

Tipo de elemento: Article
Divisiones: Centro de Investigación y Desarrollo en Ciencias de la Salud
Usuario depositante: Editor Repositorio
Creadores:
CreadorEmailORCID
Ludwig, Kerstin U.NO ESPECIFICADONO ESPECIFICADO
Ahmed, Syeda TasnimNO ESPECIFICADONO ESPECIFICADO
Böhmer, Anne C.NO ESPECIFICADONO ESPECIFICADO
Sangani, Nasim BahramNO ESPECIFICADONO ESPECIFICADO
Varghese, SheryilNO ESPECIFICADONO ESPECIFICADO
Klamt, JohannaNO ESPECIFICADONO ESPECIFICADO
Schuenke, HannahNO ESPECIFICADONO ESPECIFICADO
Gültepe, PinarNO ESPECIFICADONO ESPECIFICADO
Hofmann, AndreaNO ESPECIFICADONO ESPECIFICADO
Rubini, MicheleNO ESPECIFICADONO ESPECIFICADO
Aldhorae, Khalid AhmedNO ESPECIFICADONO ESPECIFICADO
Steegers Theunissen, Regine P.NO ESPECIFICADONO ESPECIFICADO
Rojas Martínez, AugustoNO ESPECIFICADONO ESPECIFICADO
Reiter, RudolfNO ESPECIFICADONO ESPECIFICADO
Borck, GuntramNO ESPECIFICADONO ESPECIFICADO
Knapp, MichaelNO ESPECIFICADONO ESPECIFICADO
Nakatomi, MitsushiroNO ESPECIFICADONO ESPECIFICADO
Graf, DanielNO ESPECIFICADONO ESPECIFICADO
Mangold, ElisabethNO ESPECIFICADONO ESPECIFICADO
Peters, HeikoNO ESPECIFICADONO ESPECIFICADO
Fecha del depósito: 22 Mayo 2019 15:17
Última modificación: 06 Mar 2020 21:47
URI: http://eprints.uanl.mx/id/eprint/14839

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