Finding the mutation responsible for inherited rickets in Corriedale sheep

Inherited rickets of Corriedale sheep is of simple autosomal recessive inheritance. The gross and histological lesions include segmental thickening of physes, persistence of hypertrophic chondrocytes at sites of endochondral ossification, excessive osteoclastic resorption, microfractures and wide unmineralised osteoid seams lining trabeculae and filling secondary osteons. Initial testing revealed concentrations of 25-hydroxyvitamin D₃ were normal, but those of 1,25-dihydroxyvitamin D₃ were increased in serum of affected sheep, suggesting a defect in the vitamin D receptor. However, in vitro studies on cultured skin fibroblasts revealed normal binding and function of the vitamin D receptor.

A genome-wide association study was conducted using the Illumina OvineSNP50 BeadChip. A homozygous region of 199 consecutive single-nucleotide polymorphism loci was identified in affected sheep, covering a region of 10 megabase pairs on ovine chromosome 6. Of the 91 candidate genes in this region, dentin matrix protein 1 gene (dmp1) was considered the most likely as it is known to play critical roles in osteocyte maturation and mineral metabolism. Sequencing of DNA from carriers showed a nonsense mutation 253T/C in dmp1. This T/C transition introduced a stop codon (R145X) that could truncate C-terminal amino acids. Using PCR restriction fragment length polymorphism for this mutation, genotyping showed that all affected sheep were “TT” genotypes, and phenotypically normal sheep were either “CT” or “CC”. These findings suggest that a mutation in dmp1 is responsible for inherited rickets of Corriedale sheep. A simple diagnostic test is currently being designed to identify carriers with the defective “T” alleles.     

Changes in bone structure of Corriedale sheep with inherited rickets: A peripheral quantitative computed tomography assessment

An inherited skeletal disease with gross and microscopic features of rickets has been diagnosed in Corriedale sheep in New Zealand. The aim of this study was to quantify the changes present in tibia from sheep with inherited rickets using peripheral quantitative computed tomography. In affected sheep, scans in the proximal tibia, where metaphysis becomes diaphysis, showed significantly greater trabecular bone mineral content (BMC) and bone mineral density (BMD). The sheep with inherited rickets had significantly greater BMC and bone area in the mid-diaphysis of the proximal tibia compared to control sheep. However, BMD in the mid-diaphysis was significantly less in affected sheep than in controls, due to the greater cortical area and lower voxel density values in affected sheep. From this it was concluded that the increased strain on under-mineralised bone in sheep with inherited rickets led to increased bone mass in an attempt to improve bone strength.     

An outbreak of rickets in Corriedale sheep: evidence for a genetic aetiology

CASE HISTORY: A skeletal disease characterised by lameness, limb deformities and reduced growth rate occurred over two successive years in lambs born on a commercial sheep farm in Marlborough. A genetic aetiology was considered likely following exclusion of other known causes of rickets and because of the progressive nature of the disease, even after affected animals were transferred to another property. CLINICAL FINDINGS: Affected lambs appeared normal at birth but developed clinical signs during the first 2 months of life. The most severely affected animals either died or were euthanised within the first year of life, but some survived to breeding age. Serum biochemistry revealed hypocalcaemia, hypophosphataemia and increased concentrations of 1,25 dihydroxyvitamin D. The mean serum 25 hydroxyvitamin D concentration was similar to that of control lambs. PATHOLOGICAL FINDINGS: Gross lesions included enlarged costochondral junctions, bilateral irregularity of articular surfaces on humeral heads due to collapse of subchondral bone, thickened cortices in long bones and irregular thickening of physeal cartilages. Microscopically, tongues of hypertrophic chondrocytes extended from physes into metaphyseal regions; metaphyseal trabeculae were thick, disorganised and often lined by wide osteoid seams. Osteoclastic activity was excessive both in cortical and trabecular bone. DIAGNOSIS: Inherited rickets in Corriedale sheep. CLINICAL RELEVANCE AND CONCLUSIONS: This disease is likely to be present in several Corriedale sheep flocks in New Zealand and may have been misdiagnosed as arthritis or other diseases causing lameness and/or poor growth. A defect in end-organ responsiveness to 1,25 dihydroxyvitamin D is the likely mechanism. This disease of sheep may be a useful model for studying vitamin D metabolism and the treatment of inherited forms of rickets in human beings.     

Suspected inherited cerebellar neuroaxonal dystrophy in collie sheep dogs

A cerebellar neuroaxonal dystrophy in working collie sheep dogs from two properties in New Zealand and one property in Australia is described. Clinical signs developed from 2–4 months of age and included hypermetria, wide-based stance, difficulty in maintaining balance, intention tremor and ataxia. Numerous spheroids, associated with mild Wallerian degeneration, were present in the central cerebellar, adjacent peduncular and folia white matter, and associated cerebellar roof and lateral vestibular nuclei. The history of several affected pups in litters from successive matings of the same sire and dam is suggestive of an autosomal recessive mode of inheritance.     

Suspected inherited cerebellar neuroaxonal dystrophy in collie sheep dogs

A cerebellar neuroaxonal dystrophy in working collie sheep dogs from two properties in New Zealand and one property in Australia is described. Clinical signs developed from 2-4 months of age and included hypermetria, wide-based stance, difficulty in maintaining balance, intention tremor and ataxia. Numerous spheroids, associated with mild Wallerian degeneration, were present in the central cerebellar, adjacent peduncular and folia white matter, and associated cerebellar roof and lateral vestibular nuclei. The history of several affected pups in litters from successive matings of the same sire and dam is suggestive of an autosomal recessive mode of inheritance.     

Normal vitamin D receptor function with increased expression of 25-hydroxyvitamin D(3)-24-hydroxylase in Corriedale sheep with inherited rickets

A likely inherited disease with gross and microscopic features of rickets has been recognised in Corriedale sheep in New Zealand, and a defect in end-organ responsiveness to vitamin D has been proposed as a likely mechanism. The aim of the present study was to characterize the mode of inheritance and determine the disease mechanism. Breeding trials showed that the mode of inheritance was autosomal recessive. Serum chemistry testing using different methodology and studies in cultured skin fibroblasts did not support our previous hypothesis of a defect in end-organ responsiveness. The studies revealed normal serum 1,25-dihydroxyvitamin D concentrations, normal vitamin D receptor function, and the presence of 24-hydroxylase mRNA in cells from affected sheep, even without induction by 1,25-dihydroxyvitamin D₃. In addition, osteocalcin mRNA expression was similar in both affected and control sheep. It was concluded that increased expression of 25-hydroxyvitamin D₃-24-hydroxylase, the enzyme that breaks down vitamin D, may be involved in the pathogenesis of inherited rickets in Corriedale sheep, but its role requires further clarification.     

Congenital hydranencephaly and arthrogryposis of Corriedale sheep

SUMMARY: A syndrome of congenital malformations in Corriedale sheep characterised by brachygnathia inferior, campylognathia, tetraemlic arthrogryposis, kyphoscoliosis, hydranencephaly and hypoplasia of the brain stem, cerebellum and spinal cord occurring in various combinations is described. Histologically there was generalised hypomyelinogenesis and hypoplasia of the central nervous system with neurogenic atrophy of skeletal muscle. The syndrome resembled that caused by congenital infection with Akabane virus, however, serological, pathological and epidemiological data indicated that Akabane virus was not involved. The results of a breeding trial suggested that the disorder may be transmitted with an autosomal recessive mode of inheritance.     

Suspected Lyme borreliosis in sheep.

Two cases of suspected Lyme borreliosis in lambs are described. The clinical signs observed resemble those described for Lyme borreliosis in dogs and horses. The lambs were approximately six months old and came from two different flocks in a district heavily infested with Ixodes ricinus ticks. The lambs had pronounced lameness in one leg, generally bad condition and poor appetite. They had high serum levels of IgG antibodies to Borrelia burgdorferi when tested in an ELISA. The other lambs in the flocks were negative to B burgdorferi antibodies. Attempts were made to isolate spirochaetes from one of the lambs, but were unsuccessful.     

Suspected acute salt poisoning in sheep

Extract

Salt poisoning, although well known to occur in pigs and poultry in New Zealand, does not appear to have been recorded in ruminants. The following case of losses in sheep(5 %), believed to be due to the ingestion of sea water, is therefore of interest.     

Visna-maedi-like disease associated with an ovine retrovirus infection in a Corriedale sheep

A visna-maedi-like disease was found in a Corriedale sheep from which a retrovirus sharing the group antigen of visna-progressive pneumonia virus was isolated from lung, brain, and spleen. Clinically, the sheep had acute neurologic signs and dyspnea. Pathologic examination showed lesions similar to both visna and maedi. In the lung, there was a patchy interstitial pneumonia with marked lymphoid hyperplasia. Changes in the central nervous system were necrotizing nonsuppurative encephalitis of the brain stem, poliomyelitis of the cervical cord, and ependymitis and subependymal gliosis of the ventricles. Histologically, the central nervous system lesions seemed to have arisen sequentially, perhaps in response to bursts of virus replication as the agent underwent possible antigenic mutation. The severe lesions in both the central nervous system and lungs suggested a virus strain with dual tropism.     

An inherited cataract in New Zealand Romney sheep

A bilateral cataract was noted to occur in sheep on a New Zealand Romney stud. Extensive breeding trials showed that this defect was inherited as an autosomal dominant. As such this form of cataract is of minimal importance to the sheep industry as control is merely by culling affected individuals.     

An inherited cataract in New Zealand Romney sheep

A bilateral cataract was noted to occur in sheep on a New Zealand Romney stud. Extensive breeding trials showed that this defect was inherited as an autosomal dominant. As such this form of cataract is of minimal importance to the sheep industry as control is merely by culling affected individuals.     

A suspected inherited neuromuscular disease in dorset down sheep

Extract

Madam:– This is the first report in New Zealand of what appears to be an inherited neuromuscular disease in Dorset Down sheep. During two successive breeding seasons approximately 20% of ewes in a stud flock comprising 54 ewes and one ram gave birth to lambs showing pronounced weakness of either both hind or all four limbs. Over 20 male or female single, twin, or one of a pair of twin lambs were affected. From birth these animals were alert and could raise their heads but they were unable to stand. Characteristically they lay with hindlimbs tucked under their bodies and forelimbs splayed sideways. Most affected lambs were slaughtered but those which were hand reared made a partial recovery. One such animal examined at five weeks of age showed pronounced flexion of the tarsal joints so that it walked on its hocks. The forelimbs were held unusually straight and the carpal joints occasionally knuckled over when the lamb walked. The limb joints were fully mobile upon manipulation and the hindlimbs were able to bear weight for short periods of time.     

微卫星标记与考力代羊体重体尺性状遗传关系研究

本试验用单标记法研究考力代绵羊1号染色体ILSTS004~CSSM004和BM6506~MCM130之间的12个微卫星位点ILSTS004、MCMA008、MNS0094、CSSM004、BM6505、BMS4008、CSRD0298、TGLA415、BM8246、RM0509、URB0038、MCM0130,与其绵羊初生重、断奶重、体重(8月龄)、体高、体长、胸围、管围的遗传关系,结果ILSTS004位点不同基因型对初生重影响极显著(P<0·01)、对体重影响显著(P<0·05),CSSM004位点对体长影响显著(P<0·05),其余位点对体重等性状无显著影响(P>0·05)。其中,ILSTS004位点:基因型101099个体的初生重显著高于基因型095093(P<0·05),基因型101099个体的体重显著高于基因型103103(P<0·05);CSSM004基因型196196个体的体长显著大于基因型202202(P<0·05)。提示在1号染色体微卫星位点ILSTS004附近可能存在影响绵羊初生重、体重的数量性状位点(QTL),ILSTS004可作为其遗传标记之一;在CSSM004附近可能存在影响体长的QTL,CSSM004可作为其遗传标记之一。