A Deletion in the N-Myc Downstream Regulated Gene 1 (NDRG1) Gene in Greyhounds with Polyneuropathy

The polyneuropathy of juvenile Greyhound show dogs shows clinical similarities to the genetically heterogeneous Charcot-Marie-Tooth (CMT) disease in humans. The pedigrees containing affected dogs suggest monogenic autosomal recessive inheritance and all affected dogs trace back to a single male. Here, we studied the neuropathology of this disease and identified a candidate causative mutation. Peripheral nerve biopsies from affected dogs were examined using semi-thin histology, nerve fibre teasing and electron microscopy. A severe chronic progressive mixed polyneuropathy was observed. Seven affected and 17 related control dogs were genotyped on the 50k canine SNP chip. This allowed us to localize the causative mutation to a 19.5 Mb interval on chromosome 13 by homozygosity mapping. The NDRG1 gene is located within this interval and NDRG1 mutations have been shown to cause hereditary motor and sensory neuropathy-Lom in humans (CMT4D). Therefore, we considered NDRG1 a positional and functional candidate gene and performed mutation analysis in affected and control Greyhounds. A 10 bp deletion in canine NDRG1 exon 15 (c.1080_1089delTCGCCTGGAC) was perfectly associated with the polyneuropathy phenotype of Greyhound show dogs. The deletion causes a frame shift (p.Arg361SerfsX60) which alters several amino acids before a stop codon is encountered. A reduced level of NDRG1 transcript could be detected by RT-PCR. Western blot analysis demonstrated an absence of NDRG1 protein in peripheral nerve biopsy of an affected Greyhound. We thus have identified a candidate causative mutation for polyneuropathy in Greyhounds and identified the first genetically characterized canine CMT model which offers an opportunity to gain further insights into the pathobiology and therapy of human NDRG1 associated CMT disease. Selection against this mutation can now be used to eliminate polyneuropathy from Greyhound show dogs

Reversal of childhood idiopathic scoliosis in an adult, without surgery: a case report and literature review

<p>Abstract</p> <p>Background</p> <p>Some patients with mild or moderate thoracic scoliosis (Cobb angle <50-60 degrees) suffer disproportionate impairment of pulmonary function associated with deformities in the sagittal plane and reduced flexibility of the spine and chest cage. Long-term improvement in the clinical signs and symptoms of childhood onset scoliosis in an adult, without surgical intervention, has not been documented previously.</p> <p>Case presentation</p> <p>A diagnosis of thoracic scoliosis (Cobb angle 45 degrees) with pectus excavatum and thoracic hypokyphosis in a female patient (DOB 9/17/52) was made in June 1964. Immediate spinal fusion was strongly recommended, but the patient elected a daily home exercise program taught during a 6-week period of training by a physical therapist. This regime was carried out through 1992, with daily aerobic exercise added in 1974. The Cobb angle of the primary thoracic curvature remained unchanged. Ongoing clinical symptoms included dyspnea at rest and recurrent respiratory infections. A period of multimodal treatment with clinical monitoring and treatment by an osteopathic physician was initiated when the patient was 40 years old. This included deep tissue massage (1992-1996); outpatient psychological therapy (1992-1993); a daily home exercise program focused on mobilization of the chest wall (1992-2005); and manipulative medicine (1994-1995, 1999-2000). Progressive improvement in chest wall excursion, increased thoracic kyphosis, and resolution of long-standing respiratory symptoms occurred concomitant with a >10 degree decrease in Cobb angle magnitude of the primary thoracic curvature.</p> <p>Conclusion</p> <p>This report documents improved chest wall function and resolution of respiratory symptoms in response to nonsurgical approaches in an adult female, diagnosed at age eleven years with idiopathic scoliosis.</p

Mitochondrial phylogeography of baboons (Papio spp.) – Indication for introgressive hybridization?

<p>Abstract</p> <p>Background</p> <p>Baboons of the genus <it>Papio </it>are distributed over wide ranges of Africa and even colonized parts of the Arabian Peninsula. Traditionally, five phenotypically distinct species are recognized, but recent molecular studies were not able to resolve their phylogenetic relationships. Moreover, these studies revealed para- and polyphyletic (hereafter paraphyletic) mitochondrial clades for baboons from eastern Africa, and it was hypothesized that introgressive hybridization might have contributed substantially to their evolutionary history. To further elucidate the phylogenetic relationships among baboons, we extended earlier studies by analysing the complete mitochondrial cytochrome <it>b </it>gene and the 'Brown region' from 67 specimens collected at 53 sites, which represent all species and which cover most of the baboons' range.</p> <p>Results</p> <p>Based on phylogenetic tree reconstructions seven well supported major haplogroups were detected, which reflect geographic populations and discordance between mitochondrial phylogeny and baboon morphology. Our divergence age estimates indicate an initial separation into southern and northern baboon clades 2.09 (1.54–2.71) million years ago (mya). We found deep divergences between haplogroups within several species (~2 mya, northern and southern yellow baboons, western and eastern olive baboons and northern and southern chacma baboons), but also recent divergence ages among species (< 0.7 mya, yellow, olive and hamadryas baboons in eastern Africa).</p> <p>Conclusion</p> <p>Our study confirms earlier findings for eastern Africa, but shows that baboon species from other parts of the continent are also mitochondrially paraphyletic. The phylogenetic patterns suggest a complex evolutionary history with multiple phases of isolation and reconnection of populations. Most likely all these biogeographic events were triggered by multiple cycles of expansion and retreat of savannah biomes during Pleistocene glacial and inter-glacial periods. During contact phases of populations reticulate events (i.e. introgressive hybridization) were highly likely, similar to ongoing hybridization, which is observed between East African baboon populations. Defining the extent of the introgressive hybridization will require further molecular studies that incorporate additional sampling sites and nuclear loci.</p

Evidence that disease-induced population decline changes genetic structure and alters dispersal patterns in the Tasmanian devil

Infectious disease has been shown to be a major cause of population declines in wild animals. However, there remains little empirical evidence on the genetic consequences of disease-mediated population declines, or how such perturbations might affect demographic processes such as dispersal. Devil facial tumour disease (DFTD) has resulted in the rapid decline of the Tasmanian devil, Sarcophilus harrisii , and threatens to cause extinction. Using 10 microsatellite DNA markers, we compared genetic diversity and structure before and after DFTD outbreaks in three Tasmanian devil populations to assess the genetic consequences of disease-induced population decline. We also used both genetic and demographic data to investigate dispersal patterns in Tasmanian devils along the east coast of Tasmania. We observed a significant increase in inbreeding (F IS pre/post-disease −0.030/0.012, P <0.05; relatedness pre/post-disease 0.011/0.038, P =0.06) in devil populations after just 2–3 generations of disease arrival, but no detectable change in genetic diversity. Furthermore, although there was no subdivision apparent among pre-disease populations ( θ =0.005, 95% confidence interval (CI) −0.003 to 0.017), we found significant genetic differentiation among populations post-disease ( θ =0.020, 0.010–0.027), apparently driven by a combination of selection and altered dispersal patterns of females in disease-affected populations. We also show that dispersal is male-biased in devils and that dispersal distances follow a typical leptokurtic distribution. Our results show that disease can result in genetic and demographic changes in host populations over few generations and short time scales. Ongoing management of Tasmanian devils must now attempt to maintain genetic variability in this species through actions designed to reverse the detrimental effects of inbreeding and subdivision in disease-affected populations

Translational neuropsychiatry of genetic and neurodevelopmental animal models of schizophrenia

Psychiatric symptoms are subjective by nature and tend to overlap between different disorders. The modelling of a neuropsychiatric disorder therefore faces challenges because of missing knowledge of the fundamental pathophysiology and a lack of accurate diagnostics. Animal models are used to test hypotheses of aetiology and to represent the human condition as close as possible to increase our understanding of the disease and to evaluate new targets for drug discovery. In this review, genetic and neurodevelopmental animal models of schizophrenia are discussed with respect to behavioural and neurophysiological findings and their association with the clinical condition. Only specific animal models of schizophrenia may ultimately lead to novel diagnostic approaches and drug discovery. We argue that molecular biomarkers are important to improve animal to human translation since behavioural readouts lack the necessary specificity and reliability to assess human psychiatric symptoms