Mutations in BMP4 are associated with subepithelial, microform, and overt cleft lip

Abstract

Cleft lip with or without cleft palate (CL/P) is a complex trait with evidence that the clinical spectrum includes both microform and subepithelial lip defects. We identified missense and nonsense mutations in the BMP4 gene in 1 of 30 cases of microform clefts, 2 of 87 cases with subepithelial defects in the orbicularis oris muscle (OOM), 5 of 968 cases of overt CL/P, and 0 of 529 controls. These results provide confirmation that microforms and subepithelial OOM defects are part of the spectrum of CL/P and should be considered during clinical evaluation of families with clefts. Furthermore, we suggest a role for BMP4 in wound healing.

Figure 1

Subepithelial and Microform Defects Ultrasound Images of the Proband S91C, Who Has an Orbicularis Oris Muscle Defect, and Her Husband Ultrasound images are taken in the transverse plane; the top of the image corresponds to anterior structures; OOM = orbicularis oris muscle; AR = alveolar ridge. The arrowhead in (A) points to the discontinuity in the OOM of the proband (A). In contrast, note the continuous appearance of the husband's OOM (B). (C) A child (A346V) has left microform CLP. (D) His father (A346V) has subtle right microform cleft lip and a “heart-shaped” bifid uvula. See Table S1 for a summary of the cases and controls sequenced for BMP4.

Figure 2

Comparative Amino Acid Sequence Alignment of Vertebrate BMP4 and Mutations of BMP4 in Humans The top row shows a schematic diagram of the human BMP4 gene with the positions of exons and their translated protein domains. Both exon 3 and exon 4 are in the translated region. Filled green is the TGF beta propeptide domain and violet is the TGF beta domain. Gray background in the alignment indicates regions of complete amino acid identity across species. Comparative amino acid alignment follows the order of Homo sapiens (Human [NP_001193]), Pan troglodytes (Chimpanzee [XP_509954]), Bos taurus (Cow [NP_001039342]), Rattus norvegicus (Rat [NP_036959]), Canis familiaris (Dog [XP_851628]), Gallus gallus (Chicken [NP_990568]), Xenopus tropicalis (Frog [NP_001017034]), and Danio rerio (Zebrafish [NP_571417]). C is Cleft lip and palate; oo is orbicularis oris defect; M is Microform cleft.