CANT1 mutation is also responsible for Desbuquois dysplasia, type 2 and Kim variant

Abstract

Background Desbuquois dysplasia (DD) is a recessively inherited condition characterised by short stature, generalised skeletal dysplasia and advanced bone maturation. DD is both clinically and radiographically heterogeneous, and two subtypes have been distinguished based on the presence (type 1) or absence (type 2) of an accessory metacarpal bone. In addition, an apparently distinct variant without additional metacarpal bone but with short metacarpals and long phalanges (Kim variant) has been described recently. Mutations in the gene that encodes for CANT1 (calcium-activated nucleotidase 1) have been identified in a subset of patients with DD type 1. Methods A series of 11 subjects with DD from eight families (one type 1, two type 2, five Kim variant) were examined for CANT1 mutations by direct sequencing of all coding exons and their flanking introns. Results Eight distinct mutations were identified in seven families (one type 1, one type 2 and all 5 Kim variant): three were nonsense and five were missense. All missense mutations occurred at highly conserved amino acids in the nucleotidase conserved regions of CANT1. Measurement of nucleotidase activity in vitro showed that the missense mutations were all associated with loss-of-function. Conclusion The clinical-radiographic spectrum produced by CANT1 mutations must be extended to include DD type 2 and Kim variant. While presence or absence of an additional metacarpal ossification centre has been used to distinguish subtypes of DD, this sign is not a distinctive criterion to predict the molecular basis in DD.

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

“…The other patients were of non-consanguineous and compound heterozygotes of the mutations. 6 Their phenotypes were all diagnosed as DBQD Kim variant as previously reported. 3 One Japanese (CT1) and one Korean (CT2) subject from general populations who were found to have c.676G4A in a heterozygous state in the previous study were also examined.…”

“…However, the carrier frequency of the common mutation is considerably high in Korean. From our experience, 6 the frequency of the CANT1 mutation is speculated as about double of that of the common mutation. Thereafter, prevalence of DBQD is B1/35 000 in Korean and B1/600 000 in Japanese; the former is far higher than our impression in daily practice.…”

“…c.676G4A was also found in 1/754 Japanese and 1/187 Korean controls in a heterozygous state. 6 These results led us consider that the mutation may be inherited from a common founder(s) among Japanese and Korean. To test the hypotheisis, we examined haplotypes of the patients around CANT1 and found that the mutation was on a common haplotype background of B500 kb.…”

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

“…12 Very recently, mutations in the CANT1 gene have also been found associated with the DBQD type 2, as well as with the so called 'Kim variant' of DBQD. 13 …”

Estudo genético-clínico das displasias esqueléticas, com enfoque nas osteocondrodisplasias com acometimento do esqueleto axial, associado ao envolvimento epifisário e/ou metafisário

“…A DDES, causada por mutações em homozigose ou heterozigose composta no gene CANT1, é caracterizada por baixa estatura pré e pós-natal (estatura abaixo de -5 desvios padrão), frouxidão ligamentar, luxações de múltiplas articulações (algumas congênitas), face média aplainada, micrognatia, fenda palatina e escoliose progressiva (Furuichi et al, 2011). O principal achado radiográfico é o hipercrescimento do trocanter inferior, que em conjunto com a face inferior do colo femural, assume um formato "em chave inglesa" ou monkey wrench/Swedish key.…”