Craniofacial Shape Variation in Twist1^+/− Mutant Mice

Abstract

Craniosynostosis (CS) is a relatively common birth defect resulting from the premature fusion of one or more cranial sutures. Human genetic studies have identified several genes in association with CS. One such gene that has been implicated in both syndromic (Saethre-Chotzen syndrome) and nonsyndromic forms of CS in humans is TWIST1. In this study, a heterozygous Twist1 knock out (Twist1 1/2 ) mouse model was used to study the craniofacial shape changes associated with the partial loss of function. A geometric morphometric approach was used to analyze landmark data derived from microcomputed tomography scans to compare craniofacial shape between 17 Twist1 1/2 mice and 26 of their Twist1 1/1 (wild type) littermate controls at 15 days of age. The results show that despite the purported wide variation in synostotic severity, Twist1 1/2 mice have a consistent pattern of craniofacial dysmorphology affecting all major regions of the skull. Similar to SaethreChotzen, the calvarium is acrocephalic and wide with an overall brachycephalic shape. Mutant mice also exhibited a shortened cranial base and a wider and shorted face, consistent with coronal CS associated phenotypes. The results suggest that these differences are at least partially the direct result of the Twist1 haploinsufficiency on the developing craniofacial skeleton. This study provides a quantitative phenotype complement to the developmental and molecular genetic research previously done on Twist1. These results can be used to generate further hypotheses about the effect of Twist1 and premature suture fusion on the entire craniofacial skeleton. Anat Rec,

Genetic advances in craniosynostosis

“…TWIST1 mutations were found in six out of 43 Korean patients (14%) with uni/bicoronal CS, including a single nonsyndromic patient (2.3%) [Ko et al, 2012]. As a further confirmation of the somewhat specific role of TWIST1 in coronal suture patterning, Twist+/− mutant mice exhibit a brachycephalic skull consistent with the involvement of the coronal suture in craniofacial dysmorphism [Parsons et al, 2014]. Based on these facts TWIST1 mutational analysis should be considered for patients with coronal CS even in the absence of clear syndromic traits.…”

Thyroxine Exposure Effects on the Cranial Base

“…Skulls were stabilized using a custom cradle, and reconstructed with NRecon v1.6.4.8 (BrukermicroCT, Kontich, Belgium) as previously described [38]. Threshold settings were set to capture bone volume within the skull.…”

Effects of In Utero Thyroxine Exposure on Murine Cranial Suture Growth

“…Scans were obtained on 181 animals (Male = 42.8%; Female = 43.3%; Undetermined = 13.9%). Mouse skulls were reconstructed with NRecon v1.6.4.8 (BrukermicroCT, Kontich, Belgium) as previously described and imported into Amira v5.0 where it was exposed to a Gaussian Smoothing image filter (r50.3 in X, Y, and Z dimensions; isometric kernel size53) to reduce extraneous noise in the images [47]. Threshold settings were then set to only visualize bone volume within the skull.…”