Abstract
Craniosynostosis (CS) is a disorder that involves the premature ossification of one or more cranial sutures. Our research team has described a naturally occurring rabbit model of CS with a variable phenotype and unknown etiology. Restriction-site associated DNA (RAD) sequencing is a genomic sampling method for identifying genetic variants in species with little or no existing sequence data. RAD sequencing data was analyzed using a mixed linear model to identify single nucleotide polymorphisms (SNPs) associated with disease occurrence and onset in the rabbit model of CS. SNPs achieving a genome-wide significance of p ≤ 5 x 10−8 were identified on chromosome 2 in association with disease occurrence and on chromosomes 14 and 19 in association with disease onset. Genotyping identified a coding variant in fibroblast growth factor binding protein 1 (FGFBP-1) on chromosome 2 and a non-coding variant upstream of integrin alpha 3 (ITGA3) on chromosome 19 that associated with disease occurrence and onset, respectively. Retrospective analysis of patient data revealed a significant inverse correlation between FGFBP-1 and ITGA3 transcript levels in patients with coronal CS. FGFBP-1 and ITGA3 are genes with roles in early development that warrant functional study to further understand suture biology.
Highlights
During normal development the cranial sutures consist of a fibrous and highly cellular connective tissue that bridges the bones of the cranial vault
To identify susceptibility loci associated with disease phenotype in the CS rabbit genomic DNAs obtained from EOS CS rabbits (N = 12), DOS CS rabbits (N = 12), and in-colony normal rabbits (ICN; N = 22) were subjected to Restriction-site associated DNA (RAD) sequencing
This yield is comparable to the values obtained using RAD sequencing in other vertebrate and plant species including geese, rainbow trout, soybean, and barley [27,28,29,30]
Summary
During normal development the cranial sutures consist of a fibrous and highly cellular connective tissue that bridges the bones of the cranial vault These joints function as growth sites until the brain reaches its mature volume. Pathway analysis of gene expression data has implicated extracellular matrix (ECM) interactions as differentially regulated gene networks in cases of single-suture synostosis [4]. Despite this progress, the molecular basis for disease remains uncertain in approximately 80% of patients affected by CS. Recent work suggests a modifying allele may determine the age-of-onset for coronal suture fusion [9], though the genetic etiology remains undefined. The current study was designed to identify the loci responsible for occurrence and the timing of suture fusion within the synostotic rabbit
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