Identification of CANT1 Mutations in Desbuquois Dysplasia
ABSTRACT Desbuquois dysplasia is a severe condition characterized by short stature, joint laxity, scoliosis, and advanced carpal ossification with a delta phalanx. Studying nine Desbuquois families, we identified seven distinct mutations in the Calcium-Activated Nucleotidase 1 gene (CANT1), which encodes a soluble UDP-preferring nucleotidase belonging to the apyrase family. Among the seven mutations, four were nonsense mutations (Del 5' UTR and exon 1, p.P245RfsX3, p.S303AfsX20, and p.W125X), and three were missense mutations (p.R300C, p.R300H, and p.P299L) responsible for the change of conserved amino acids located in the seventh nucleotidase conserved region (NRC). The arginine substitution at position 300 was identified in five out of nine families. The specific function of CANT1 is as yet unknown, but its substrates are involved in several major signaling functions, including Ca2+ release, through activation of pyrimidinergic signaling. Importantly, using RT-PCR analysis, we observed a specific expression in chondrocytes. We also found electron-dense material within distended rough endoplasmic reticulum in the fibroblasts of Desbuquois patients. Our findings demonstrate the specific involvement of a nucleotidase in the endochondral ossification process.
Full-textDOI: · Available from: Lihadh Al-Gazali, Sep 26, 2015
- SourceAvailable from: Katia Sol-Church
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- "''Monkey wrench'' appearance of pelvis þ þ þ þ Flat acetabular roof þ þ þ þ Elevated greater trochanter (age related) þ þ þ þ Proximal fibular overgrowth þ þ þ À Advanced carpal/tarsal bone age þ þ þ þ Hands/feet Accessory ossification proximal phalanx, second digit þ À À À Bifid distal phalanx of the thumb þ À À À Delta phalanx/delta-like phalanx þ À À À Phalangeal dislocation þ À þ À Elongated appearance of fingers/toes À À þ À Other criteria Brachydactyly with ''stub thumbs'' þ þ À þ Brachymetacarpalia þ þ þ þ Wide metaphyses þ þ þ þ Flat epiphyses þ þ þ þ Vertebral body indentations/coronal or sagittal clefts þ þ þ À Wide anterior ribs þ þ À þ Enlarged first metatarsal þ þ þ À Coxa valga þ þ þ À Medial deviation of the foot þ þ þ À Present study major features Developmental delay/learning disability þ/À þ /À À þ Ligamentous laxity þ þ þ þ Patellae dislocation/lateral displacement À À þ þ CANT1 mutation þ þ þ À (CANT1) that encodes, an extracellular protein expressed in chondrocytes and implicated in endoplasmic reticulum metabolism have been determined to cause DBD types 1, 2, and Kim [Huber et al., 2009; Faden et al., 2010; Furuichi et al., 2011]. Some of the clinical and radiographic findings in our patients, such as the short femoral necks and flat acetabular roofs, advanced bone age and patellar dislocations do resemble DBD, or a Desbuquois-like phenotype. "
ABSTRACT: We describe a series of seven male patients from six different families with skeletal dysplasia, characteristic facial features, and developmental delay. Skeletal findings include patellar dislocation, short tubular bones, mild metaphyseal changes, brachymetacarpalia with stub thumbs, short femoral necks, shallow acetabular roofs, and platyspondyly. Facial features include: a flattened midface with broad nasal bridge, cleft palate or bifid uvula and synophrys. All of the patients demonstrated pre-school onset of a cognitive developmental delay with a shortened attention span. Some of the cognitive delay was masked by a warm and engaging personality. We posit that these individuals have a newly recognized syndrome characterized by the described features. There is some phenotypic overlap between these patients and Desbuquois dysplasia; however molecular testing demonstrated that this is a distinct disorder. Given the family information available for each patient, we are suspicious that the constellation of findings reported herein could be an X-linked recessive syndrome.American Journal of Medical Genetics Part A 08/2012; 158A(8):1815-22. DOI:10.1002/ajmg.a.35445 · 2.16 Impact Factor
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- "Considering the clinical overlap between conditions due to CHST3 mutations and DD, we finally questioned whether CANT1 may play a role in proteoglycan and hyaluronic acid metabolism. For this purpose, we metabolically labeled with 3H-glucosamine and 35SO42− fibroblasts from two previously published DD type 1 patients with CANT1 homozygous mutations (c.899G>A (p.Arg300His) and c.734delC (p.Pro245Argfs*4) [Huber et al., 2009]) and four age matched controls. No significant difference in proteoglycan synthesis was observed when cells were incubated in basal medium due to huge variability among controls (P = 0.214) (Fig. 2A); however, in the presence of β-d-xyloside, a compound which enhances synthesis and secretion of chondroitin and dermatan sulfate chains acting as a chain initiator [Sobue et al., 1987], GAG synthesis in patient cells was significantly reduced compared to control cell lines (P < 0.0001) (Fig. 2B). "
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.Human Mutation 08/2012; 33(8):1261-6. DOI:10.1002/humu.22104 · 5.14 Impact Factor
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- "Homozygosity mapping localized the gene responsible to chromosome 17q25.3 [Faivre et al., 2003] and recently a mutation in exon4 of CANT1 gene was identified in this family (Table 6) [Huber et al., 2009]. "
ABSTRACT: The United Arab Emirates inhabitants are ethnically diverse, with ancestries from Arabia, Persia, Baluchistan, and Africa. However, the majority of the current five million inhabitants are expatriates from the Asian subcontinent, Middle Eastern, African, and European countries. Consanguineous marriages within most UAE subpopulations are still the norm, leading to the formation of isolates and higher frequencies of recessive conditions. The UAE is ranked sixth in terms of prevalence of birth defects, with more than 270 genetic disorders reported in the national population. The UAE has high frequencies of blood disorders including thalassemias, sickle cell disease, and G6PD. In addition, certain genetic conditions are relatively common including cystic fibrosis, Joubert, and Meckel syndromes. Furthermore, numerous rare congenital malformations and metabolic disorders have been reported. We review the single gene disorders that have been studied at the molecular level in the UAE (which currently stand at 76) and compile the mutations found. Several novel (p.S2439fs) mutations have been reported including c.7317delA in NF1, c.5C>T (p.A2V) in DKC1, c.1766T>A (p.I589N) in TP63, and c.2117G>T (p.R706L) in VLDLR. We hope that this review will form the basis to establish a UAE mutations database and serve as a model for the collection of mutations of a country.Human Mutation 05/2010; 31(5):505-20. DOI:10.1002/humu.21232 · 5.14 Impact Factor