MRPL53, a New Candidate Gene for Orofacial Clefting, Identified Using an eQTL Approach.

Autor: Masotti C; 1 Department of Genetics and Evolutionary Biology, University of São Paulo, São Paulo, SP, Brazil.; 2 Molecular Oncology Center, Hospital Sírio Libanês, São Paulo, SP, Brazil., Brito LA; 1 Department of Genetics and Evolutionary Biology, University of São Paulo, São Paulo, SP, Brazil., Nica AC; 3 Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.; 4 Institute for Genetics and Genomics in Geneva (iGE3), University of Geneva, Geneva, Switzerland.; 5 Swiss Institute of Bioinformatics, Geneva, Switzerland., Ludwig KU; 6 Institute of Human Genetics, University of Bonn, Bonn, Germany.; 7 Department of Genomics, Life&Brain Center, University of Bonn, Bonn, Germany., Nunes K; 1 Department of Genetics and Evolutionary Biology, University of São Paulo, São Paulo, SP, Brazil., Savastano CP; 1 Department of Genetics and Evolutionary Biology, University of São Paulo, São Paulo, SP, Brazil., Malcher C; 1 Department of Genetics and Evolutionary Biology, University of São Paulo, São Paulo, SP, Brazil., Ferreira SG; 1 Department of Genetics and Evolutionary Biology, University of São Paulo, São Paulo, SP, Brazil., Kobayashi GS; 1 Department of Genetics and Evolutionary Biology, University of São Paulo, São Paulo, SP, Brazil., Bueno DF; 1 Department of Genetics and Evolutionary Biology, University of São Paulo, São Paulo, SP, Brazil., Alonso N; 8 Department of Plastic Surgery, University of São Paulo Medical School, São Paulo, SP, Brazil., Franco D; 9 Department of Plastic Surgery, Hospital Clementino Braga Filho, Federal University of Rio de Janeiro Medical School, Rio de Janeiro, RJ, Brazil., Rojas-Martinez A; 10 Department of Biochemistry and Molecular Medicine, School of Medicine, and Centro de Investigación y Desarrollo en Ciencias de la Salud, Universidad Autonoma de Nuevo Leon, Monterrey, Mexico., Dos Santos SE; 11 Institute of Biological Sciences, Federal University of Pará, Belém, PA, Brazil., Galante PA; 2 Molecular Oncology Center, Hospital Sírio Libanês, São Paulo, SP, Brazil., Meyer D; 1 Department of Genetics and Evolutionary Biology, University of São Paulo, São Paulo, SP, Brazil., Hünemeier T; 1 Department of Genetics and Evolutionary Biology, University of São Paulo, São Paulo, SP, Brazil., Mangold E; 6 Institute of Human Genetics, University of Bonn, Bonn, Germany., Dermitzakis ET; 3 Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.; 4 Institute for Genetics and Genomics in Geneva (iGE3), University of Geneva, Geneva, Switzerland.; 5 Swiss Institute of Bioinformatics, Geneva, Switzerland., Passos-Bueno MR; 1 Department of Genetics and Evolutionary Biology, University of São Paulo, São Paulo, SP, Brazil.
Jazyk: angličtina
Zdroj: Journal of dental research [J Dent Res] 2018 Jan; Vol. 97 (1), pp. 33-40. Date of Electronic Publication: 2017 Oct 20.
DOI: 10.1177/0022034517735805
Abstrakt: A valuable approach to understand how individual and population genetic differences can predispose to disease is to assess the impact of genetic variants on cellular functions (e.g., gene expression) of cell and tissue types related to pathological states. To understand the genetic basis of nonsyndromic cleft lip with or without cleft palate (NSCL/P) susceptibility, a complex and highly prevalent congenital malformation, we searched for genetic variants with a regulatory role in a disease-related tissue, the lip muscle (orbicularis oris muscle [OOM]), of affected individuals. From 46 OOM samples, which are frequently discarded during routine corrective surgeries on patients with orofacial clefts, we derived mesenchymal stem cells and correlated the individual genetic variants with gene expression from these cultured cells. Through this strategy, we detected significant cis-eQTLs (i.e., DNA variants affecting gene expression) and selected a few candidates to conduct an association study in a large Brazilian cohort (624 patients and 668 controls). This resulted in the discovery of a novel susceptibility locus for NSCL/P, rs1063588, the best eQTL for the MRPL53 gene, where evidence for association was mostly driven by the Native American ancestry component of our Brazilian sample. MRPL53 (2p13.1) encodes a 39S protein subunit of mitochondrial ribosomes and interacts with MYC, a transcription factor required for normal facial morphogenesis. Our study illustrates not only the importance of sampling admixed populations but also the relevance of measuring the functional effects of genetic variants over gene expression to dissect the complexity of disease phenotypes.
Databáze: MEDLINE