Molecular basis for pseudo vitamin D-deficiency rickets in the Hannover pig

Chavez, L. S.; Serda, Rita E.; Choe, S; Davidi, L.; Harmeyer, J.; Omdahl, John L.

doi:10.1016/s0955-2863(03)00077-9

Cited by 15 publications

(14 citation statements)

References 30 publications

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“…64 At the molecular level, VDDR I in the Hannover pig is associated with one of two different deletions in the P450C1 coding region. 30 One involves a deletion of 173 base pairs and the other, a deletion of 329 base pairs, both of which lead to a frame shift mutation and a premature stop codon. 30 The result produces conformational changes that make the enzyme ineffectual owing to loss of the heme-binding region and other domains.…”

Section: Pigsmentioning

confidence: 99%

“…30 The result produces conformational changes that make the enzyme ineffectual owing to loss of the heme-binding region and other domains. 30 The authors hypothesized that a mRNA processing error may have caused the deletions, given that they occurred at mRNA processing sites. 30 …”

Section: Pigsmentioning

confidence: 99%

“…30 The authors hypothesized that a mRNA processing error may have caused the deletions, given that they occurred at mRNA processing sites. 30 …”

Section: Pigsmentioning

confidence: 99%

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Vitamin D Metabolism and Rickets in Domestic Animals

2010

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Rickets and osteomalacia are increasing in prevalence in people because of cultural practices, breast-feeding, decreased sun exposure, and increased sunscreen usage. Several hereditary forms of rickets owing to either renal phosphate wasting or defects in vitamin D metabolism are also reported in people. Rickets is well recognized in domestic animals, but published reports are not always supported by microscopic findings, and diagnoses based on clinical signs and radiology are unreliable. Most cases in domestic animals are caused by dietary deficiency of either vitamin D or phosphorus, but occasional inherited forms are reported in pigs, sheep, cats, and dogs. There is variation between species in susceptibility to dietary vitamin D and phosphorus deficiency and in the ability to manufacture vitamin D in their skin. A number of mouse models have been discovered or created to study human skeletal diseases and skeletal homeostasis. With the discovery that vitamin D is involved in not only calcium and phosphorus homeostasis but also in the immune system and cancer, there is great potential for new and existing animal models to generate valuable information about vitamin D and its many functions. This review presents an overview of vitamin D metabolism and rickets in domestic and laboratory animals and makes comparisons where appropriate with the disease in humans. Keywords bone, rickets, vitamin D, phosphorus, genetic diseasesRickets is a classic metabolic bone disease of humans and animals, first described in the first and second centuries. 158,165 With the discovery that vitamin D could prevent rickets, the prevalence of this disease in developed countries plummeted; however, it still occurs. In fact, the prevalence of rickets and vitamin D insufficiency is increasing in people of all ages in the developed world, due in part to decreased sunlight exposure and widespread sunscreen usage. 88 The disease is well recognized in animals, but published reports are uncommon and sometimes confusing.The pathogenesis of rickets involves impaired mineralization of physeal and epiphyseal cartilage during endochondral ossification and of newly formed osteoid. Most cases in domestic animals are caused by dietary deficiency of either vitamin D or phosphorus, but occasional inherited forms are reported. 109,200 Osteomalacia is caused by a failure of newly formed osteoid to mineralize, but it occurs in adults after closure of growth plates. 109In this article, we review vitamin D metabolism and rickets, with reference to the disease in domestic animals but presenting comparison with the disease in humans where appropriate. Biology of Vitamin D Activation of Vitamin DVitamin D is available from two sources: isomerization of 7-dehydrocholesterol (7-DHC) in the skin to vitamin D 3 following exposure to ultraviolet light or from ingestion of vitamin D 2 or D 3 in the diet. Only a few foods, including cod liver oil and fatty fish such as salmon and sardines, naturally contain high concentrations of vitamin D 3 .49 Vitamin D 2 i...

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Section: Pigsmentioning

confidence: 99%

Section: Pigsmentioning

confidence: 99%

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Vitamin D Metabolism and Rickets in Domestic Animals

2010

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“…The autosomalrecessive genetic disorder pseudo vitamin D-deficiency rickets has been linked to mutations in the P450C1 gene locus on human chromosome 12 (12q13.2-13.3) that are associated with an inefficient or dysfunctional P450C1 enzyme in humans (65,124,139) and the pseudo vitamin D-deficiency rickets Hannover pig model (29).…”

Section: Deletion Of P450c1 Activitymentioning

confidence: 99%

HYDROXYLASEENZYMES OF THEVITAMIND PATHWAY: Expression, Function, and Regulation

Omdahl

Morris²,

May³

2002

Annu. Rev. Nutr.

283

184

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Vitamin D is a secosteroid that is metabolically activated and degraded through the actions of three cytochrome P450 hydroxylase enzymes. Bioactivation occurs through the sequential actions of cytochromes P450C25 and P450C1, resulting in synthesis of the pleiotropic hormone 1,25-dihydroxyvitamin D (1,25VD), which regulates over 60 genes whose actions include those associated with calcium homeostasis and immune responses as well as cellular growth, differentiation, and apoptosis. Inactivation of 1,25VD occurs by C23/C24 oxidation pathways that are catalyzed by the multifunctional cytochrome P450C24 enzyme. Both P450C1 and P450C24 are highly regulated enzymes whose differential expression is controlled in response to numerous cellular modulatory agents such as parathyroid hormone (PTH), calcitonin, interferon gamma, calcium, phosphorus, and pituitary hormones as well as the secosteroid hormone 1,25VD. Most thoroughly studied at the molecular level are the actions of PTH to upregulate P450C1 gene expression and 1,25VD to induce the expression of P450C24. The regulatory action of PTH is mediated through the protein kinase A pathway and involves the phosphorylation of transcription factors that function at the proximal promoter of the P450C1 gene. The upregulation of P450C24 by 1,25VD has both a rapid nongenomic and a slower genomic component that are functionally linked. The rapid response involves protein kinase C and mitogen-activated protein kinase (MAPK) pathways that direct the phosphorylation of nuclear transcription factors. The slower genomic actions are linked to the binding of 1,25VD to the vitamin D receptor (VDR) and the interaction of the VDR-1,25VD complex with its heterodimer partner retinoid-X-receptor and associated coactivators. The regulatory complex is assembled on vitamin D response elements in the proximal promoter of the P450C24 gene and functions to increase the transcription rate.

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“…28 Genetic examples include defective vitamin D metabolism and impaired renal function that interferes with excretion of excess phosphorus. 2,6,28 Rickets and osteomalacia have a similar pathogenesis resulting in decreased or defective bone mineralization. Rickets manifests as failure of endochondral ossification in growing bone.…”

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confidence: 99%

Rickets

et al. 2012

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Rickets can be attributed to nutritional, genetic, hormonal, or toxic disturbances and is classified as a metabolic bone disease. Rickets is most often associated with inappropriate dietary levels of calcium, phosphorus, and/or vitamin D. During a 27-month period (January 2010 through March 2012), the Iowa State University Veterinary Diagnostic Laboratory investigated causes of sudden, unexpected death and lameness in growing pigs throughout the Midwestern United States. Clinical observations from 17 growing pig cases included weakness, lameness, reluctance to move, muscle fasciculations and/or tremors, tetany, and death. Ribs were weak, soft, and bent prior to breaking; rachitic lesions were apparent at costochondral junctions in multiple cases. Acute and/or chronic bone fractures were also noted in multiple bones. Failure of endochondral ossification, expanded physes, infractions, thin trabeculae, and increased osteoclasts were noted microscopically. Decreased bone ash and serum 25(OH)D(3), combined with clinical and microscopic evaluation, confirmed a diagnosis of vitamin D-dependent rickets in all cases. In 3 cases, disease was linked to a specific nutrient supplier that ultimately resulted in a voluntary feed recall; however, most cases in the current investigation were not associated with a particular feed company. The present report describes vitamin D-associated rickets and its importance as a potential cause of weakness, lameness, muscle fasciculations, recumbency or sudden unexpected death in swine, and describes appropriate samples and tests for disease diagnosis.

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Molecular basis for pseudo vitamin D-deficiency rickets in the Hannover pig

Cited by 15 publications

References 30 publications

Vitamin D Metabolism and Rickets in Domestic Animals

Vitamin D Metabolism and Rickets in Domestic Animals

HYDROXYLASEENZYMES OF THEVITAMIND PATHWAY: Expression, Function, and Regulation

Rickets

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