Progressive retinal atrophy (PRA) is a common cause of blindness in many dog breeds. It is most often inherited as a simple Mendelian trait, but great genetic heterogeneity has been demonstrated both within and between breeds. In many breeds the genetic cause of the disease is not known, and until now, the Old Danish Pointing Dog (ODP) has been one of those breeds. ODP is one of the oldest dog breeds in Europe. Seventy years ago the breed almost vanished, but today a population still exists, primarily in Denmark but with some dogs in Germany and Sweden. PRA has been diagnosed in ODP since the late 1990s. It resembles late onset PRA in other dog breeds, and it is inherited as an autosomal recessive trait. In the present study, we performed whole-genome sequencing and identified a single base insertion (c.3149_3150insC) in exon 1 of C17H2orf71. This is the same mutation previously found to cause PRA in Gordon Setters and Irish Setters, and it was later found in Tibetan Terrier, Standard Poodle and the Polski Owczarek Nizinny. The presence of the mutation in such a diverse range of breeds indicates an origin preceding creation of modern dog breeds. Hence, we screened 262 dogs from 44 different breeds plus four crossbred dogs, and can subsequently add Miniature Poodle and another polish sheepdog, the Polski Owczarek Podhalanski, to the list of affected breeds.

Liver fibrosis is a common wound-healing response to chronic liver injuries, including alcoholic or drug toxicity, persistent viral infection, and genetic factors. Myofibroblastic transdifferentiation (MTD) is the pivotal event during liver fibrogenesis, and research in the past few years has identified key mediators and molecular mechanisms responsible for MTD of hepatic stellate cells (HSCs). HSCs are undifferentiated cells which play an important role in liver regeneration. Recent evidence demonstrates that HSCs derive from mesoderm and at least in part via septum transversum and mesothelium, and HSCs express markers for different cell types which derive from multipotent mesenchymal progenitors. There is a regulatory commonality between differentiation of adipocytes and that of HSC, and the shift from adipogenic to myogenic or neuronal phenotype characterizes HSC MTD. Central of this shift is a loss of expression of the master adipogenic regulator peroxisome proliferator activated receptor γ (PPARγ). Restored expression of PPARγ and/or other adipogenic transcription genes can reverse myofibroblastic HSCs to differentiated cells. Vertebrate Wnt and Drosophila wingless are homologous genes, and their translated proteins have been shown to participate in the regulation of cell proliferation, cell polarity, cell differentiation, and other biological roles. More recently, Wnt signaling is implicated in human fibrosing diseases, such as pulmonary fibrosis, renal fibrosis, and liver fibrosis. Blocking the canonical Wnt signal pathway with the co-receptor antagonist Dickkopf-1 (DKK1) abrogates these epigenetic repressions and restores the gene PPARγ expression and HSC differentiation. The identified morphogen mediated epigenetic regulation of PPARγ and HSC differentiation also serves as novel therapeutic targets for liver fibrosis and liver regeneration. In conclusion, the Wnt signaling promotes liver fibrosis by enhancing HSC activation and survival, and we herein discuss what we currently know and what we expect will come in this field in the next future.

BACKGROUND: The value of genotyping to predict variant phenotypes in patients with phenylalanine hydroxylase (Pah) deficiency is a matter of debate. However, there exists no comprehensive population relationship study focused on the Han Chinese.
METHODS: We analyzed genotype-phenotype correlation for 186 different genotypes in 338 unrelated Chinese patients harboring 109 different Pah mutations. Two systems were used in this process. The first was a phenotype prediction system based on arbitrary values (AV) attributed to each mutation. The second was a pair-wise correlation analysis. The observed phenotype for AV analysis was the corresponding metabolic phenotype stratified according to the pretreatment phenylalanine (Phe) value.
RESULTS: We found that the observed phenotype matched the predicted phenotype in 54.41% of 272 patients for whom AV information was available; the highest degree of concordance (61.83%) was found in patients with null/null genotypes, whereas the lowest \"concordance rate\" (32.69%) was observed for patients with expected mild-PKU phenotype. There are repeated inconsistencies for such mutations as R241C, R243Q, R261Q, V388M, V399V, R408Q, A434D and EX6-96A>G which are associated with variable phenotypes in patients with identical genotype. Significant correlations were disclosed between pretreatment Phe values and predicted residual activity (r=-0.45643, P<0.0001) or AV sum (r=-0.59523, P<0.0001).
CONCLUSIONS: Our study supports the notion that the Pah mutation genotype is the main determinant of metabolic phenotype in most patients in a particular population, and provided novel insights into the values that underpin the subsequent treatment and the prognosis of PKU in Chinese.