ARHGAP29 Mutation Is Associated with Abnormal Oral Epithelial Adhesions.

Document Type


Publication Date



Alleles, Animals, Blotting, Western, Cell Adhesion, Cleft Lip, Cleft Palate, Codon, Codon, Nonsense, Embryonic Development, Exons, GTPase-Activating Proteins, Genome-Wide Association Study, Humans, Mice, Mice, Inbred Strains, Phenotype, Point Mutation, Polymorphism, Single Nucleotide

JAX Location

Reprint Collection

JAX Source

J Dent Res 2017 Oct; 96(11):1298-1305





First Page


Last Page








Nonsyndromic cleft lip and/or palate (NSCL/P) is a prevalent birth defect of complex etiology. Previous studies identified mutations in ARHGAP29 associated with an increased risk for NSCL/P. To investigate the effects of ARHGAP29 in vivo, we generated a novel murine allele by inserting a point mutation identified in a patient with NSCL/P. This single-nucleotide variation of ARHGAP29 translates to an early nonsense mutation (K326X), presumably resulting in loss-of-function (LoF). Embryos from Arhgap29(K326X/+) intercrosses were harvested at various time points. No homozygous Arhgap29(K326X) animals were found in the 45 analyzed litters, assessed as early as embryonic day 8.5 (e8.5). Coronal sectioning of e13.5 and e14.5 heads revealed that 59% of Arhgap29(K326X/+) mice ( n = 37) exhibited improper epithelial contact between developing oral structures, while none were observed in wild types ( n = 10). In addition, Arhgap29(K326X/+) embryos exhibited a significantly higher percentage of maxillary epithelium in contact with mandibular epithelium. Immunofluorescent analyses of the periderm and oral adhesions revealed the presence of Arhgap29 in periderm cells. These cells were p63 negative, keratin 17 positive, and keratin 6 positive and present at sites of adhesion, although occasionally disorganized. Oral adhesions did not appear to impair palatogenesis, as all analyzed Arhgap29(K326X/+) embryos showed confluent palatal mesenchyme and epithelium at e18.5 ( n = 16), and no mice were found with a cleft at birth. Collectively, our data demonstrate that ARHGAP29 is required for embryonic survival and that heterozygosity for LoF variants of Arhgap29 increases the incidence and length of oral adhesions at a critical time point during orofacial development. In conclusion, we validate the LoF nature of the human K326X mutation in vivo and reveal a previously unknown effect of Arhgap29 in murine craniofacial development. J Dent Res 2017 Oct; 96(11):1298-1305.

Please contact the Joan Staats Library for information regarding this document.