title: Haploinsufficiency of interferon regulatory factor 6 alters brain morphology in the mouse.
abstract: Orofacial clefts are among the commonest birth defects. Among many genetic contributors to orofacial clefting, Interferon Regulatory Factor 6 (IRF6) is unique since mutations in this gene cause Van der Woude (VWS), the most common clefting syndrome. Furthermore, variants in IRF6 contribute to increased risk for non-syndromic cleft lip and/or palate (NSCL/P). Our previous work shows that individuals with either VWS or NSCL/P may have cerebral anomalies (larger anterior, smaller posterior regions), and a smaller cerebellum. The objective of this study was to test the hypothesis that disrupting Irf6 in the mouse will result in quantitative brain changes similar to those reported for humans with VWS and NSCL/P. Male mice heterozygous for Irf6 (Irf6(gt1/+); n = 9) and wild-type (Irf6(+/+) ; n = 6) mice at comparable age underwent a 4.7-T MRI scan to obtain quantitative measures of cortical and subcortical brain structures. There was no difference in total brain volume between groups. However, the frontal cortex was enlarged in the Irf6(gt1/+) mice compared to that of wild types (P = 0.028) while the posterior cortex did not differ. In addition, the volume of the cerebellum of Irf6(gt1/+) mice was decreased (P = 0.004). Mice that were heterozygous for Irf6 showed a similar pattern of brain anomalies previously reported in humans with VWS and NSCL/P. These structural differences were present in the absence of overt oral clefts. These results support a role for IRF6 in brain morphometry and provide evidence for a potential genetic link to abnormal brain development in orofacial clefting.
authors.affiliation: Department of Psychiatry, University of Iowa, Iowa City, Iowa.
authors.forename: Andrea
authors.initials: A
authors.lastname: Aerts
authors.forename: Ian
authors.initials: I
authors.lastname: DeVolder
authors.forename: Seth M
authors.initials: SM
authors.lastname: Weinberg
authors.forename: Dan
authors.initials: D
authors.lastname: Thedens
authors.forename: Martine
authors.initials: M
authors.lastname: Dunnwald
authors.forename: Brian C
authors.initials: BC
authors.lastname: Schutte
authors.forename: Peg
authors.initials: P
authors.lastname: Nopoulos
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology*; D002971:Cleft Lip / Q000235:genetics; D002972:Cleft Palate / Q000235:genetics; D004195:Disease Models, Animal; D056726:Genetic Association Studies; D057895:Haploinsufficiency; D006579:Heterozygote; D050835:Interferon Regulatory Factors / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D010641:Phenotype
chemical_list: C528250:IRF6 protein, mouse; D050835:Interferon Regulatory Factors
keywords: IRF6; brain development; magnetic resonance imaging; mouse model; oral clefts