Heterozygosity of the Celtic polled locus in Canadian scurred beef cattle

Polled cattle are preferable to horned or scurred animals because they are safer for handling and cause less bruising. Although DNA testing can determine horned/polled genotype, scurs may appear in polled animals. The inheritance of scurs is complex because it is a sex-influenced trait that interacts with the polled locus. We demonstrate that in 685 purebred and crossbred Canadian beef cattle, all 153 scurred animals were heterozygous polled at the Celtic variant. In addition, male obligate carriers of scurs were smooth polled when homozygous for the polled mutation. Scurred and non-scurred males were sequenced for five genes (CTDNEP1, SHBG, SOX15, FGF11, and DHRS7C) within the scur candidate region on BTA19 that are functionally related to bone development and hormone regulation. Multipoint linkage analysis was conducted using 18 microsatellite markers and two informative variants (DHRS7C g.29594018G>C and CTDNEP1 c.462G>A) in the scurred families and further supported mapping on BTA19 between BMS2142 (logarithm of the odds (LOD) = 5.42) and IDVGA46 (LOD = 3.47). These data indicate epistatic interactions between the scurred and polled loci and emphasise the necessity for a scurred DNA test to assist purebred beef producers in eradicating the scur trait.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Contribution of growth differentiation factor 6-dependent cell survival to early-onset retinal dystrophies

Retinal dystrophies are predominantly caused by mutations affecting the visual phototransduction system and cilia, with few genes identified that function to maintain photoreceptor survival. We reasoned that growth factors involved with early embryonic retinal development would represent excellent candidates for such diseases. Here we show that mutations in the transforming growth factor- (TGF-) ligand Growth Differentiation Factor 6, which specifies the dorso-ventral retinal axis, contribute to Leber congenital amaurosis. Furthermore, deficiency of gdf6 results in photoreceptor degeneration, so demonstrating a connection between Gdf6 signaling and photoreceptor survival. In addition, in both murine and zebrafish mutant models, we observe retinal apoptosis, a characteristic feature of human retinal dystrophies. Treatment of gdf6-deficient zebrafish embryos with a novel aminopropyl carbazole, P7C3, rescued the retinal apoptosis without evidence of toxicity. These findings implicate for the first time perturbed TGF- signaling in the genesis of retinal dystrophies, support the study of related morphogenetic genes for comparable roles in retinal disease and may offer additional therapeutic opportunities for genetically heterogeneous disorders presently only treatable with gene therapy

GDF6, a Novel Locus for a Spectrum of Ocular Developmental Anomalies

Colobomata represent visually impairing ocular closure defects that are associated with a diverse range of developmental anomalies. Characterization of a chromosome 8q21.2-q22.1 segmental deletion in a patient with chorioretinal coloboma revealed elements of nonallelic homologous recombination and nonhomologous end joining. This genomic architecture extends the range of chromosomal rearrangements associated with human disease and indicates that a broader spectrum of human chromosomal rearrangements may use coupled homologous and nonhomologous mechanisms. We also demonstrate that the segmental deletion encompasses GDF6, encoding a member of the bone-morphogenetic protein family, and that inhibition of gdf6a in a model organism accurately recapitulates the proband’s phenotype. The spectrum of disorders generated by morpholino inhibition and the more severe defects (microphthalmia and anophthalmia) observed at higher doses illustrate the key role of GDF6 in ocular development. These results underscore the value of integrated clinical and molecular investigation of patients with chromosomal anomalies