title: Regulatory variant in FZD6 gene contributes to nonsyndromic cleft lip and palate in an African-American family.
abstract: Nonsyndromic cleft lip with or without cleft palate (NSCLP) is a common birth defect affecting 135,000 newborns worldwide each year. While a multifactorial etiology has been suggested as the cause, despite decades of research, the genetic underpinnings of NSCLP remain largely unexplained. In our previous genome-wide linkage study of a large NSCLP African-American family, we identified a candidate locus at 8q21.3-24.12 (LOD = 2.98). This region contained four genes, Frizzled-6 (FZD6), Matrilin-2 (MATN2), Odd-skipped related 2 (OSR2) and Solute Carrier Family 25, Member 32 (SLC25A32). FZD6 was located under the maximum linkage peak. In this study, we sequenced the coding and noncoding regions of these genes in two affected family members, and identified a rare variant in intron 1 of FZD6 (rs138557689; c.-153 + 432A>C). The variant C allele segregated with NSCLP in this family, through affected and unaffected individuals, and was found in one other NSCLP African-American family. Functional assays showed that this allele creates an allele-specific protein-binding site and decreases promoter activity. We also observed that loss and gain of fzd6 in zebrafish contributes to craniofacial anomalies. FZD6 regulates the WNT signaling pathway, which is involved in craniofacial development, including midfacial formation and upper labial fusion. We hypothesize, therefore, that alteration in FZD6 expression contributes to NSCLP in this family by perturbing the WNT signaling pathway.
authors.affiliation: Department of Pediatrics, University of Texas Medical School at Houston Houston, Texas ; Graduate School of Biomedical Sciences, University of Texas Health Science Center Houston, Texas.
authors.forename: Nevena
authors.initials: N
authors.lastname: Cvjetkovic
authors.affiliation: Department of Pediatrics, University of Texas Medical School at Houston Houston, Texas.
authors.forename: Lorena
authors.initials: L
authors.lastname: Maili
authors.affiliation: Department of Pediatrics, University of Texas Medical School at Houston Houston, Texas ; Graduate School of Biomedical Sciences, University of Texas Health Science Center Houston, Texas.
authors.forename: Katelyn S
authors.initials: KS
authors.lastname: Weymouth
authors.affiliation: Department of Pediatrics, University of Texas Medical School at Houston Houston, Texas.
authors.forename: S Shahrukh
authors.initials: SS
authors.lastname: Hashmi
authors.affiliation: Boston Children's Hospital Boston, Massachusetts.
authors.forename: John B
authors.initials: JB
authors.lastname: Mulliken
authors.affiliation: Department of Pediatrics, Northwestern University Feinberg School of Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago Research Center Chicago, Illinois.
authors.forename: Jacek
authors.initials: J
authors.lastname: Topczewski
authors.affiliation: Graduate School of Biomedical Sciences, University of Texas Health Science Center Houston, Texas ; University of Texas School of Dentistry at Houston Houston, Texas.
authors.forename: Ariadne
authors.initials: A
authors.lastname: Letra
authors.affiliation: Department of Pediatrics, University of Texas Medical School at Houston Houston, Texas.
authors.forename: Qiuping
authors.initials: Q
authors.lastname: Yuan
authors.affiliation: Dr. John T. Macdonald Department of Human Genetics, Hussman Institute for Human Genomics, University of Miami Miller School of Medicine Miami, Florida.
authors.forename: Susan H
authors.initials: SH
authors.lastname: Blanton
authors.affiliation: Department of Pediatrics, University of Texas Medical School at Houston Houston, Texas.
authors.forename: Eric C
authors.initials: EC
authors.lastname: Swindell
authors.affiliation: Department of Pediatrics, University of Texas Medical School at Houston Houston, Texas ; Graduate School of Biomedical Sciences, University of Texas Health Science Center Houston, Texas ; University of Texas School of Dentistry at Houston Houston, Texas.
authors.forename: Jacqueline T
authors.initials: JT
authors.lastname: Hecht
keywords: Frizzled-6; WNT pathway; nonsyndromic cleft lip and palate; regulatory variant