In other species: dog , pig

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 264700 (trait) , 609506 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2009

Cross-species summary: Vitamin D (cholecalciferol) is synthesised in the skin from 7-dehydrocholesterol by the action of UV radiation from sunlight. Cholecalciferol, however, has very little biological activity: it requires two hydroxylations in order to become (biologically) active. The first hydroxylation, catalysed by cholecalciferol 25-hydroxylase, occurs in the liver. The second of these hydroxylations occurs in the kidney under the action of the enzyme 25-alpha-hydroxycholecalciferol 1-hydroxylase. The resultant active form of vitamin D (called 1,25-dihydroxycholecalciferol or 1,25(OH)sub2D) is a steroid hormone that plays a vital role in whole-body calcium homeostasis. Vitamin D-deficieny rickets, type 1A (previously known as Pseudo-vitamin D deficiency rickets) is an inherited deficiency of the 1-hydroxylase enzyme, due to mutations in the gene that encodes this enzyme, namely CYP27B1. As expected, this deficiency results in clinical signs indistinguishable from those seen in individuals suffering from non-genetic lack of vitamin D, most commonly resulting from a dietary deficiency of calcium or insufficient exposure to sunlight. The clinical signs of rickets (inherited and non-genetic) arise from defects in calcium homeostasis. The most noticeable effects include a failure of calcification of bones (leading to bowing of limbs) and delayed dentition.

Molecular basis: Giesen et al. (2009) reported an affected cat with two mutations in the CYP27B1 gene: a missense mutation (Val75Met) and a single base deletion (731delG), the latter of which is more likely to be the cause of the clinical signs. Grahn et al. (2012) reported a second causative mutation also in exon 4 of the same gene: "exon 4 G637T nonsense mutation results in a premature protein truncation, changing a glutamic acid to a stop codon, E213X, likely causing the clinical presentation of rickets."

Associated gene: