In other species: domestic cat , pig

Categories: Skeleton phene (incl. short stature & teeth)

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 264700 (trait) , 609506 (gene)

Links to relevant human diseases in MONDO:

• MONDO:0020723: vitamin D-dependent rickets, type 1A

Mendelian trait/disorder: yes

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2023

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.

Species-specific symbol: VDDR type 1A

Molecular basis: Rhodin et al. (2023) "A truncating mutation in the 1α-hydroxylase gene (CYP27B1) was identified by genome sequence analysis of the pugs with VDDR type 1A."

Clinical features: Rhodin et al. (2023) investigated related pugs from 2 litters: "Three pugs had clinical signs including, lameness, bone deformities, and dyspnea. One other pug was found dead. Radiographs of 2 affected pugs, 5 and 6 months old, showed generalized widening, and irregular margination of the physes of both the appendicular and the axial skeleton with generalized decrease in bone opacity and bulbous swelling of the costochondral junctions. Two pugs had low serum calcium and 1,25 (OH)2D3 concentrations. Test results further indicated secondary hyperparathyroidism with adequate concentrations of 25-hydroxyvitamin D."

Pathology: Rhodin et al. (2023) "Necropsy [of affected pugs] revealed tongue-like projections of cartilage extending into the metaphysis consistent with rickets, loss of metaphyseal mineralization and lung pathology."

Breeds: Pug (Dog) (VBO_0201089), Saint Bernard (Dog) (VBO_0201160).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: