Desbuquois Dysplasia 1, Kim Variant
In a Japanese patient, born of consanguineous parents, with the Kim variant of Desbuquois dysplasia-1 (DBQD1; see 251450), Furuichi et al. (2011) identified a homozygous 676G-A transition in the CANT1 gene, resulting in a val226-to-met (V226M) substitution in a highly conserved residue. Four additional patients, of Japanese or Korean origin, with this phenotype also carried the V226M substitution in compound heterozygosity with another pathogenic mutation in the CANT1 gene (see, e.g., 613165.0014). The V226M mutation was found in 1 of 754 Japanese controls and in 1 of 187 Korean controls. Four of the 5 patients had been reported by Kim et al. (2010) as having a milder form of the disorder. All had normal cognitive development, but most showed delayed motor development. All had short stature and multiple joint dislocations and laxity, particularly affecting the knee. Radiographic criteria included a 'monkey wrench' appearance of the proximal femora, epimetaphyseal dysplasia at the knees, and advanced carpal/tarsal bone age. Radiographic studies showed short metacarpals with normal or slightly elongated proximal and middle phalanges and short distal phalanges, resulting in a nearly equal length of the second to fourth or fifth finger. None had an accessory ossification center or thumb anomalies. After about age 15 years, radiographs showed precocious degenerative arthritis in the carpal bones and interphalangeal joints. The hip joints showed premature degenerative osteoarthritis with age. All patients also had kyphoscoliosis with vertebral endplate irregularities and narrowing of the disc space; the older ones developed progressive degenerative spondylosis. In vitro functional expression studies in COS-7 cells showed that the V226M mutant protein was stably expressed and secreted normally, but had decreased enzyme activity compared to wildtype. The findings indicated that the so-called Kim variant of DBQD is allelic to types 1 and 2 DBQD.
By haplotype analysis of the 5 families with the V226M mutation reported by Furuichi et al. (2011), Dai et al. (2011) demonstrated a founder effect for this mutation among Japanese and Korean individuals. The age of the mutation was estimated at about 1,420 years, around the time of the late Kofun era.
Epiphyseal Dysplasia, Multiple, 7
In a female patient of Latino origin (R01-152A) with multiple epiphyseal dysplasia (EDM7; 617719), Balasubramanian et al. (2017) identified homozygosity for the V226M mutation in the CANT1 gene. The authors stated that although radiographs of the EDM patient showed some overlapping features with DBQD, the overall phenotype was milder and clearly distinct from DBQD. They noted that 1 previously reported family with the Kim variant of DBQD was also homozygous for V226M (Furuichi et al., 2011), but stated that radiographic data for a full comparison of the phenotype with their EDM case had not been published.
