Cleft lip in oculodentodigital dysplasia suggests novel roles for connexin43.
Oculodentodigital Dysplasia (ODDD) is a rare syndrome involving anomalies in eye, tooth, and digit formation, caused by mutations in CX43/GJA1. In addition to classic dental features, ODDD includes oral and craniofacial accessory symptoms such as characteristic facial appearance and cleft palate. However, there have been no reports of ODDD accompanied by cleft lip. Herein we report, for the first time, a male, sporadic, Asian proband presenting bilateral cleft lip. By direct sequence analysis, our proband was diagnosed as having ODDD with a heterozygous mutation, codon 142 G>A in GJA1 and CX43E48K. We excluded the possibility of pathogenic mutations in B3GALTL, BMP4, TFAP2A, PVRL1, IRF6, and MSX1. To address how CX43/GJA1 is related to cleft lip, we performed immunohistochemistry using mouse and human mid-facial tissue. CX43 expression was detected in the nasal compartment and nasal and maxillary processes at murine developmental stage E12.5. Furthermore, CX43 expression was found in the epithelial tissue inside the human subepithelial cleft lip that completes epithelial fusion. Therefore, we suggest that CX43/GJA1 is involved in lip formation. Our case report of ODDD with a bilateral cleft lip suggests that CX43/GJA1 might be a novel candidate gene for syndromic cleft lip.
The First Department of Oral and Maxillofacial Surgery, Osaka University Graduate School of Dentistry, Osaka, Japan. k-tenno@ace.ocn.ne.jp
K
K
Amano
M
M
Ishiguchi
T
T
Aikawa
M
M
Kimata
N
N
Kishi
T
T
Fujimaki
A
A
Murakami
M
M
Kogo
D000015:Abnormalities, Multiple / Q000235:genetics; D000225:Adenine; D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics; D002675:Child, Preschool; D002971:Cleft Lip / Q000235:genetics*; D018031:Connexin 43 / Q000235:genetics*; D004848:Epithelium / Q000473:pathology; D005091:Exons / Q000235:genetics; D005124:Eye Abnormalities / Q000235:genetics*; D005385:Fingers / Q000002:abnormalities*; D005700:Galactosyltransferases / Q000235:genetics; D005964:Glucosyltransferases / Q000235:genetics; D018698:Glutamic Acid / Q000235:genetics; D006147:Guanine; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007438:Introns / Q000235:genetics; D008046:Lip / Q000473:pathology; D008239:Lysine / Q000235:genetics; D008297:Male; D051379:Mice; D023421:Models, Animal; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D014071:Tooth Abnormalities / Q000235:genetics*; D050656:Transcription Factor AP-2 / Q000235:genetics
C525809:BMP4 protein, human; D055415:Bone Morphogenetic Protein 4; D018031:Connexin 43; C500216:GJA1 protein, human; C493673:TFAP2A protein, human; D050656:Transcription Factor AP-2; D018698:Glutamic Acid; D006147:Guanine; C514116:B3GLCT protein, human; D005700:Galactosyltransferases; D005964:Glucosyltransferases; D000225:Adenine; D008239:Lysine