Mutation of CANT1 causes Desbuquois dysplasia

Abstract

Desbuquois dysplasia is an autosomal recessive dysplasia characterized by severe growth restriction and distinct hand and proximal femur appearance in addition to cognitive impairment. The critical interval for this disease has been mapped to 17q25.3 using homozygosity mapping. We have identified a newborn with classical features of the disease whose parents are first cousins. Assuming genetic homogeneity of this disorder, we were able to narrow the critical interval to a region that only contained 10 annotated genes by combining the results of our homozygosity mapping with those of others. Serial sequencing of the genes contained within the interval revealed a 5 bp duplication in Calcium-Activated Nucleotidase 1 gene (CANT1), consistent with the very recent report by Huber et al. [Huber et al. (2009); Am J Hum Genet 85:706-710]. This report cements the role of CANT1 in the causation of this dysplasia and demonstrates the high value of even single cases in the setting of genetically homogeneous disorders when homozygosity mapping is used.

A founder mutation of CANT1 common in Korean and Japanese Desbuquois dysplasia

“…Recently, Huber et al 4 identified mutations in the gene encoding the calcium-activated nucleotidase 1 (CANT1) in DBQD type 1, which is followed by Faden et al 5 We also found CANT1 mutations in DBQD type 2 and Kim variant. In our series, we identified CANT1 mutations in all seven patients from five unrelated families with DBQD Kim variant, and all patients had c.676G4A (p.V226M).…”

Desbuquois dysplasia type I and fetal hydrops due to novel mutations in the CANT1 gene

“…12,13,21 Sixteen different mutations were identified in these families (Table 1). Here we report the first mutations found in patients of German descent.…”

“…This is consistent with previous reports that suggest a male preponderance of 2:3 F/M in DBQD type 1, 3 and of 1:4 (4:17) F/M in 'early lethal DBQD' . 1,3,6,9,12,21,22 A good explanation for a male preponderance is still lacking; one possibility would be a better prenatal survival of male fetuses. 15 …”

Ca2+-activated Nucleotidase 1, a Novel Target Gene for the Transcriptional Repressor DREAM (Downstream Regulatory Element Antagonist Modulator), Is Involved in Protein Folding and Degradation

“…Inclusion bodies containing proteinaceous material within distended ER cisternae have been found in fibroblasts from patients suggesting the possibility of a role for CANT1 in the endochondral ossification pro-cess (23,(57)(58)(59). One report, actually, postulated that the CANT1 deficiency might interfere with the availability of UDPsugars needed for proteoglycan synthesis, but no demonstration was provided (23).…”