Transforming growth factor-alpha (TGFA): genomic structure, boundary sequences, and mutation analysis in nonsyndromic...

Transforming growth factor-alpha (TGFA) has been proposed as a candidate gene in the etiology of nonsyndromic cleft lip with or without cleft palate (NS-CL/P) and of nonsyndromic cleft palate only (NS-CPO). Biologic support for a role of TGFA arises from its presence at high levels in the epithelial tissue of the medial edge of the palatal shelves at the time of shelf fusion in mice. Genetic support for the role of TGFA in clefting comes from the reported association of TGFA alleles with human NS-CPO and NS-CL/P. In this study we report the sequence and structure of human genomic TGFA and the search for causal TGFA mutations in 250 individuals with NS-CL/P or NS-CPO by conformational analysis of the coding sequence, splice junctions, and a portion of the 3' untranslated region strongly homologous between human and mouse. We confirm that human TGFA is composed of six exons and here report several new sequence substitutions and their frequencies. Five variants in conserved segments may represent rare causes for clefting in humans and provide support for the role of TGFA in facial morphogenesis.