The origin of the ridge and associated anomalies in Rhodesian Ridgebacks

The thesis presents studies on the inheritance of the dorsal hair ridge and Dermoid Sinus (DS) in Rhodesian Ridgeback dogs. DS is classified as a neural tube defect in humans. Thus, the dog is proven to be an excellent comparative model regarding neural tube defects. It was shown that the hair ridge is caused by an autosomal dominant mutation that predisposes for DS. Collection of material from DS-affected Rhodesian Ridgeback puppies, their parental animals and littermates was performed. Evaluation by histopathology to confirm the presence of DS was conducted. Results revealed that DS (in dogs) were located in the cervical region and that a novel skin lesion (previously referred to as DS), denoted Lipoma of the terminal filum (with skin-dimple and extra-spinal connection) (LTF) was located in the sacral region. A common genetic origin between DS and LTF was suggested. It was proposed that different types of DS and LTF may be caused by differences in FGF levels in combination with different genetic backgrounds and environmental interactions. Samples from eleven DS-affected Rhodesian Ridgebacks and nine ridgeless Rhodesian Ridgebacks were genotyped by a dog-specific genome-wide association analysis utilizing an array of 26.500 SNPs. Association between a 750 kb region and the ridge phenotype was identified. The region contained five genes FGF3, FGF4, FGF19, ORAOV1 and the 3'-end of CCND1. Further fine-mapping of the identified region, utilizing the recently developed multiple ligation-dependent genome amplification (MLGA) technique, enabled identification of the mutation causing the ridge. It was shown that the dorsal hair ridge in ridgeback dogs is caused by a 133 kb duplication of three fibroblast growth factor genes FGF3, FGF4 and FGF19 and the ORAOV1 gene. Dogs homozygous for this copy number variation mutation have an increased risk of developing DS, a neural tube-like defect. The hair ridge and development of DS is most likely caused by a gene dosage effect of increased FGF expression during a critical phase of dermal development. Nucleotide sequence analysis of the internal breakpoint of the duplication further showed that the ridge mutation was identical in Rhodesian- and Thai Ridgebacks, revealing a common origin of the mutation in the two breeds. Ridgebacks homozygote for the ridge mutation, have an increased susceptibility to develop DS and/or LTF. Further studies regarding the genetic complexity of DS and LTF will shed light on the biological complexity of these dermal lesions.