Identification of CANT1 mutations in Desbuquois dysplasia.
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.
Huber
Céline
C
Paris Descartes University, Department of Genetics and INSERM U781 and U807, Hôpital Necker Enfants Malades, 75015 Paris, France.
Oulès
Bénédicte
B
Bertoli
Marta
M
Chami
Mounia
M
Fradin
Mélanie
M
Alanay
Yasemin
Y
Al-Gazali
Lihadh I
LI
Ausems
Margreet G E M
MG
Bitoun
Pierre
P
Cavalcanti
Denise P
DP
Krebs
Alexander
A
Le Merrer
Martine
M
Mortier
Geert
G
Shafeghati
Yousef
Y
Superti-Furga
Andrea
A
Robertson
Stephen P
SP
Le Goff
Carine
C
Muda
Andrea Onetti
AO
Paterlini-Bréchot
Patrizia
P
Munnich
Arnold
A
Cormier-Daire
Valérie
V
D020121:5' Untranslated Regions; D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001120:Arginine / Q000378:metabolism; D001848:Bone Diseases, Developmental / Q000000981:diagnostic imaging / Q000235:genetics*; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D002675:Child, Preschool; D019902:Chondrocytes / Q000378:metabolism; D002886:Chromosomes, Human, Pair 17; D018389:Codon, Nonsense; D003241:Consanguinity; D018870:Endoplasmic Reticulum, Rough / Q000648:ultrastructure; D005091:Exons; D017809:Fatal Outcome; D005260:Female; D005347:Fibroblasts / Q000648:ultrastructure; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D009679:Nuclear Family; D009708:Nucleotidases / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D011859:Radiography
D020121:5' Untranslated Regions; D018389:Codon, Nonsense; D012333:RNA, Messenger; D001120:Arginine; D009708:Nucleotidases; C526909:calcium-activated nucleotidase, human; D002118:Calcium