A compound heterozygote of novel and recurrent DTDST mutations results in a novel intermediate phenotype of Desbuquois dysplasia, diastrophic dysplasia, and recessive form of multiple epiphyseal dysplasia

Miyake, Atsushi; Nishimura, Gen; Futami, Takahiro; Ohashi, Hirofumi; Chiba, Kazuhiro; Toyama, Yoshiaki; Furuichi, Tatsuya; Ikegawa, Shiro

doi:10.1007/s10038-008-0305-z

Cited by 23 publications

(26 citation statements)

References 18 publications

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“…This is shown here between DTD and rMED (Fig. 3), but it is also true for the other SLC26A6 ‐related dysplasias (between ACG1B and AO2 and between AO2 and DTD) (22–26). The spectrum of SLC26A2 ‐related dysplasias can hence be described as a continuum, while also continuously expanding (27).…”

Section: Discussionsupporting

confidence: 71%

Clinical and molecular characterization of Diastrophic Dysplasia in the Portuguese population

et al. 2010

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Barbosa M, Sousa AB, Medeira A, Lourenço T, Saraiva J, Pinto‐Basto J, Soares G, Fortuna AM, Superti‐Furga A, Mittaz L, Reis‐Lima M, Bonafé L. Clinical and molecular characterization of Diastrophic Dysplasia in the Portuguese population. SLC26A2‐related dysplasias encompass a spectrum of diseases: from lethal achondrogenesis type 1B (ACG1B; MIM #600972) and atelosteogenesis type 2 (AO2; MIM #256050) to classical diastrophic dysplasia (cDTD; MIM #222600) and recessive multiple epiphyseal dysplasia (rMED; MIM #226900). This study aimed at characterizing clinically, radiologically and molecularly 14 patients affected by non‐lethal SLC26A2‐related dysplasias and at evaluating genotype–phenotype correlation. Phenotypically, eight patients were classified as cDTD, four patients as rMED and two patients had an intermediate phenotype (mild DTD – mDTD, previously ‘DTD variant'). The Arg279Trp mutation was present in all patients, either in homozygosity (resulting in rMED) or in compound heterozygosity with the known severe alleles Arg178Ter or Asn425Asp (resulting in DTD) or with the mutation c.727‐1G>C (causing mDTD). The ‘Finnish mutation’, c.‐26+2T>C, and the p.Cys653Ser, both frequent mutations in non‐Portuguese populations, were not identified in any of the patients of our cohort and are probably very rare in the Portuguese population. A targeted mutation analysis for p.Arg279Trp and p.Arg178Ter in the Portuguese population allows the identification of approximately 90% of the pathogenic alleles.

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Section: Discussionsupporting

confidence: 71%

Clinical and molecular characterization of Diastrophic Dysplasia in the Portuguese population

et al. 2010

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“…Diagnosis of DBQD based on clinical and/or radiographic information is sometimes very difficult because of the overlapping phenotype with other diseases. 10 In DBQD patients, the founder mutation was identified in all the seven Kim variant patients, and only in the Kim variant patients to our knowledge. Therefore, this mutation may be closely related with specific phenotypes of the Kim variant; that is , accelerated carpal bone ages in childhood, short metacarpals, elongated appearance of phalanges and absence of accessory ossification center distal to the second metacarpal and thumb anomalies.…”

Section: Discussionmentioning

confidence: 66%

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

et al. 2011

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Desbuquois dysplasia (DBQD) is a severe skeletal dysplasia of autosomal recessive inheritance. DBQD is classified into types 1 and 2 based on presence or absence of hand anomalies. In a previous study, we found a CANT1 (for calcium-activated nucleotidase 1) mutation, c.676G4A in five DBQD families. They were all East Asians (Japanese or Korean). The high prevalence of the same mutation among Japanese and Korean suggested that it is a common founder mutation in the two populations. To examine a possible common founder, we examined the region around CANT1 in chromosomes with c.676G4A mutation by genotyping polymorphic markers in the region for the families. We examined their haplotypes using the family data. We identified in all families a common haplotype containing the CANT1 mutation that ranged up to 550 kb. The two unrelated carriers of the mutation in general populations in Korea and Japan could also have the haplotype. We estimated the age of the founder mutation as B1420 years (95% CI¼880-1940 years). The c.676G4A mutation of CANT1 commonly seen in Japanese and Korean DBQD should be derived from a common founder.

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“…An intermediate phenotype of DBQD, diastrophic dysplasia, and recessive multiple epiphyseal dysplasia, including the monkey wrench appearance of the proximal femora, have been identified with compound heterozygote DTDST gene mutations. 16,17 We identified three novel CANT1 gene mutations in our patients, all located within exon 2 of the gene. Two were frameshift mutations with predicted stop codons after 89 and 13 missense amino acid residues, respectively, and were expected to cause complete loss of protein function, probably through nonsense-mediated RNA decay as disease-causing mechanism.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2011

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We report on three hydropic fetuses of 17, 22 and 25 gestational weeks from three distinct families presenting with Desbuquois dysplasia type 1. All fetuses showed brachymelia and characteristic dysmorphic features. X-ray studies revealed d-shaped extraphalangeal bones and disease-specific prominence of the lesser trochanter, varying in severity with fetal age. Early lethal manifestation of the disorder was reflected in lung hypoplasia and in early death of similarly affected siblings in cases 1 and 2. All families were German Caucasians by descent. Sequence analysis of the CANT1 gene revealed two frameshift mutations, c.228_229insC and c.277_278delCT, in homozygous and compound heterozygous configuration, respectively, and a homozygously novel missense mutation, c.336C4A (p.D112E), located within a highly conserved region of exon 2. Haplotype analyses by high-resolution single-nucleotide polymorphism array showed that the haplotype associated with c.228_229insC may be traced to a single founder in the German population.

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A compound heterozygote of novel and recurrent DTDST mutations results in a novel intermediate phenotype of Desbuquois dysplasia, diastrophic dysplasia, and recessive form of multiple epiphyseal dysplasia

Cited by 23 publications

References 18 publications

Clinical and molecular characterization of Diastrophic Dysplasia in the Portuguese population

Clinical and molecular characterization of Diastrophic Dysplasia in the Portuguese population

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

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

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