Cloning of TgfßR1 and TgfßR2 and Likely Exclusion as Loci of Origin in a Rabbit Craniosynostotic Model.

ABSTRACT

OBJECTIVE: To determine whether TgfßR1 or TgfßR2 cause the craniosynostotic phenotype in a rabbit model of nonsyndromic craniosynostosis. DESIGN: Full-length TgfßR1 and TgfßR2 cDNAs were sequenced and real-time reverse-transcription polymerase chain reaction (RT-PCR) was performed to measure TgfßR1 and TgfßR2 transcripts in sutural tissue from wild type (WT) and craniosynostotic (CS) rabbits. Single nucleotide polymorphisms (SNP) were identified within TgfßR1 and TgfßR2 and were assayed for segregation with disease phenotype in 22 craniosynostotic animals. RESULTS: No structural mutations in TgfßR1 and TgfßR2 were identified in the craniosynostotic rabbits. Real-time RT-PCR quantification of TgfßR1 and TgfßR2 mRNA showed no significant difference in TgfßR1 expression between CS and WT animals, while TgfßR2 showed 50% elevation in the CS animals compared to WT (P < .05). SNP analysis within the TgfßR1 and TgfßR2 genes suggested that neither locus is linked to the craniosynostotic phenotype because no allelic combination showed any specific correlation with disease phenotype for either TgfßR1 or TgfßR2. CONCLUSIONS: Our data indicate that the craniosynostotic phenotype in this rabbit model does not arise from any structural mutation in TgfßR1 or TgfßR2, and SNP analysis also likely excludes these genes more broadly as the site of causative mutation.