Abstract
Desbuquois dysplasia (DD) is characterized by antenatal and postnatal short stature, multiple dislocations, and advanced carpal ossification. Two forms have been distinguished on the basis of the presence (type 1) or the absence (type 2) of characteristic hand anomalies. We have identified mutations in calcium activated nucleotidase 1 gene (CANT1) in DD type 1. Recently, CANT1 mutations have been reported in the Kim variant of DD, characterized by short metacarpals and elongated phalanges. DD has overlapping features with spondyloepiphyseal dysplasia with congenital joint dislocations (SDCD) due to Carbohydrate (chondroitin 6) Sulfotransferase 3 (CHST3) mutations. We screened CANT1 and CHST3 in 38 DD cases (6 type 1 patients, 1 Kim variant, and 31 type 2 patients) and found CANT1 mutations in all DD type 1 cases, the Kim variant and in one atypical DD type 2 expanding the clinical spectrum of hand anomalies observed with CANT1 mutations. We also identified in one DD type 2 case CHST3 mutation supporting the phenotype overlap with SDCD. To further define function of CANT1, we studied proteoglycan synthesis in CANT1 mutated patient fibroblasts, and found significant reduced GAG synthesis in presence of β-D-xyloside, suggesting that CANT1 plays a role in proteoglycan metabolism. Hum Mutat 33:1261–1266, 2012. © 2012 Wiley Periodicals, Inc.
Highlights
Desbuquois dysplasia [DD; MIM# 251450] is a severe autosomal recessive chondrodysplasia belonging to the multiple dislocations group [Warman et al, 2011]
We identified eight distinct calcium activated nucleotidase 1 gene (CANT1) mutations, including five novel mutations in six DD type 1 cases, one Kim variant, and one
We report here the molecular analysis of CANT1 and CHST3 in 38 DD cases
Summary
Desbuquois dysplasia [DD; MIM# 251450] is a severe autosomal recessive chondrodysplasia belonging to the multiple dislocations group (group 20 in the International Classification of Bone Disorders) [Warman et al, 2011]. First described by Desbuquois et al in 1966 [Desbuquois and Rossignol, 1966], it is characterized by prenatal and postnatal short stature (–4 SD to –10 SD), joint laxity, multiple dislocations, brachydactyly, and facial dysmorphism (prominent eyes and flat face). Some radiological features are mandatory for the diagnosis including an advanced carpal and tarsal bone age, and short long bones with “Swedish key” appearance of the proximal femur. Additional anomalies include hydramnios, cardial septal defect, lung hypoplasia, glaucoma and mental retardation. Final stature is about 114 cm (–8.5 DS) and orthopedic complications often limit the ambulation [Le Merrer et al, 1991]. Based on the presence of hand anomalies, namely, accessory ossification center distal to the second metacarpal, bifid distal phalanx, or delta phalanx of the thumb, DD type 1 has been defined while DD type 2 was distinct by the absence of hand
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