Molecular basis of a new ovine model for human 3M syndrome-2
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RESEARCH ARTICLE
Open Access
Molecular basis of a new ovine model for human 3M syndrome-2 S. A. Woolley1, S. E. Hayes1, M. R. Shariflou1, F. W. Nicholas1, C. E. Willet2, B. A. O’Rourke3 and I. Tammen1*
Abstract Background: Brachygnathia, cardiomegaly and renal hypoplasia syndrome (BCRHS, OMIA 001595–9940) is a previously reported recessively inherited disorder in Australian Poll Merino/Merino sheep. Affected lambs are stillborn with various congenital defects as reflected in the name of the disease, as well as short stature, a short and broad cranium, a small thoracic cavity, thin ribs and brachysternum. The BCRHS phenotype shows similarity to certain human short stature syndromes, in particular the human 3M syndrome-2. Here we report the identification of a likely disease-causing variant and propose an ovine model for human 3M syndrome-2. Results: Eight positional candidate genes were identified among the 39 genes in the approximately 1 Mb interval to which the disease was mapped previously. Obscurin like cytoskeletal adaptor 1 (OBSL1) was selected as a strong positional candidate gene based on gene function and the resulting phenotypes observed in humans with mutations in this gene. Whole genome sequencing of an affected lamb (BCRHS3) identified a likely causal variant ENSOARG00000020239:g.220472248delC within OBSL1. Sanger sequencing of seven affected, six obligate carrier, two phenotypically unaffected animals from the original flock and one unrelated control animal validated the variant. A genotyping assay was developed to genotype 583 animals from the original flock, giving an estimated allele frequency of 5%. Conclusions: The identification of a likely disease-causing variant resulting in a frameshift (p.(Val573Trpfs*119)) in the OBSL1 protein has enabled improved breeding management of the implicated flock. The opportunity for an ovine model for human 3M syndrome and ensuing therapeutic research is promising given the availability of carrier ram semen for BCRHS. Keywords: Whole genome sequencing, Sheep, Inherited disease, Lethal, Frameshift variant, Animal model, 3M syndrome-2
Background Brachygnathia, cardiomegaly and renal hypoplasia syndrome (BCRHS, OMIA 001595–9940) is a previously reported lethal inherited disorder in Australian Poll Merino/Merino sheep [1, 2] that, to the best of our knowledge, has not been reported in other sheep breeds in Australia. This disorder is characterized by a range of congenital defects and conforms with an autosomal * Correspondence: [email protected] 1 Faculty of Science, Sydney School of Veterinary Science, The University of Sydney, Camden, NSW 2570, Australia Full list of author information is available at the end of the article
recessive mode of inheritance based on previous pedigree information and segregation analyses [1]. Affected lambs are stillborn and the primary defects associated with this disorder are brachygnathia, cardiomegaly and renal hypoplasia, with additional skeletal defects including short stature, a short and broad cranium, a small thora
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