CANT1 – Desbuquois dysplasia 1

Desbuquois dysplasia type 1 is a severe autosomal recessive skeletal dysplasia characterized by advanced carpal ossification and distinctive hand anomalies. Pathogenic variants in CANT1 were first reported in a Japanese patient presenting with classic skeletal findings and perinatal lethality ([PMID:25252066]). Subsequent identification of biallelic frameshift and missense variants in three hydropic fetuses from German families affirmed the gene–disease relationship ([PMID:21654728]). A cohort of 11 subjects spanning type 1, type 2, and the Kim variant expanded the allelic spectrum and demonstrated loss of nucleotidase activity in vitro ([PMID:21037275]). Additional studies in patient fibroblasts confirmed reduced proteoglycan synthesis and disrupted protein dimerization for novel CANT1 mutations ([PMID:22539336]; [PMID:32907608]). Collectively, over 15 probands across four independent reports with familial segregation and concordant functional assays establish a Definitive association.

Autosomal recessive inheritance is supported by homozygous and compound heterozygous CANT1 variants in unrelated families. A homozygous 1 bp deletion was identified in the initial case report in Japan ([PMID:25252066]). Three hydropic fetuses from distinct German Caucasian families carried frameshift mutations c.228dup (p.Trp77LeufsTer13) and c.277_278del (p.Trp77LeufsTer13) in homozygous or compound heterozygous states with segregation in two families ([PMID:21654728]).

The variant spectrum includes recurrent loss-of-function alleles and pathogenic missense changes: c.228dup (p.Trp77LeufsTer13), c.277_278del (p.Trp77LeufsTer13), and c.336C>G (p.Asp112Glu) within conserved nucleotidase domains ([PMID:21654728]). A founder haplotype for c.228dup was traced to the German population, underscoring allele recurrence ([PMID:21654728]).

Functional assessment demonstrated that all tested missense mutations abolish nucleotidase activity in vitro ([PMID:21037275]). Proteoglycan synthesis assays in patient fibroblasts revealed significantly reduced glycosaminoglycan production in the presence of β-D-xyloside ([PMID:22539336]). Cloning and expression analyses showed that nonsense and missense mutations disrupt CANT1 dimerization and secretion, leading to markedly decreased enzyme activity ([PMID:32907608]).

No studies to date have presented conflicting evidence for the CANT1–Desbuquois dysplasia type 1 association.

Biallelic loss-of-function and missense variants in CANT1 impair UDP hydrolysis and proteoglycan biosynthesis, resulting in the characteristic advanced ossification and joint abnormalities. The robust genetic and functional evidence supports the use of CANT1 sequencing for definitive diagnosis and carrier screening in affected families. Key take-home: CANT1 mutations cause autosomal recessive Desbuquois dysplasia type 1 via loss-of-function mechanisms with clear diagnostic and prognostic utility.

References

• Pediatrics international : official journal of the Japan Pediatric Society • 2014 • Case of Desbuquois dysplasia type 1: potentially lethal skeletal dysplasia. PMID:25252066
• European journal of human genetics : EJHG • 2011 • Desbuquois dysplasia type I and fetal hydrops due to novel mutations in the CANT1 gene. PMID:21654728
• Journal of medical genetics • 2011 • CANT1 mutation is also responsible for Desbuquois dysplasia, type 2 and Kim variant. PMID:21037275
• Human mutation • 2012 • Further delineation of CANT1 phenotypic spectrum and demonstration of its role in proteoglycan synthesis. PMID:22539336
• Orphanet journal of rare diseases • 2020 • Cloning, expression and enzyme activity delineation of two novel CANT1 mutations: the disappearance of dimerization may indicate the change of protein conformation and even function. PMID:32907608

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