Phenotypic and genotypic overlap between atelosteogenesis type 2 and diastrophic dysplasia.

Department of Pediatrics, University of Zurich, Switzerland.
Human Genetics (Impact Factor: 4.52). 01/1997; 98(6):657-61. DOI: 10.1007/s004390050279
Source: PubMed

ABSTRACT Mutations in the diastrophic dysplasia sulfate transporter gene DTDST have been associated with a family of chondrodysplasias that comprises, in order of increasing severity, diastrophic dysplasia (DTD), atelosteogenesis type 2 (AO2), and achondrogenesis type 1B (ACG1B). To learn more about the molecular basis of DTDST chondrodysplasias and about genotype-phenotype correlations, we studied fibroblast cultures of three new patients: one with AO-2, one with DTD, and one with an intermediate phenotype (AO2/DTD). Reduced incorporation of inorganic sulfate into macromolecules was found in all three. Each of the three patients was found to be heterozygous for a c862t transition predicting a R279W substitution in the third extracellular loop of DTDST. In two patients (DTD and AO2/DTD), no other structural mutation was found, but polymerase chain reaction amplification and single-strand conformation polymorphism analysis of fibroblast cDNA showed reduced mRNA levels of the wild-type DTDST allele: these two patients may be compound heterozygotes for the "Finnish" mutation (as yet uncharacterized at the DNA level), which causes reduced expression of DTDST. The third patient (with AO2) had the R279W mutation compounded with a novel mutation, the deletion of cytosine 418 (delta c418), predicting a frameshift with premature termination. Also the delta c418 allele was underrepresented in the cDNA, in accordance with previous observations that premature stop codons reduce mRNA levels. The presence of the DTDST R279W mutation in a total of 11 patients with AO2 or DTD emphasizes the overlap between these conditions. This mutation has not been found so far in 8 analyzed ACG1B patients, suggesting that it allows some residual activity of the sulfate transporter.

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Available from: Beat Steinmann, Aug 15, 2014
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    • "In Xenopus laevis oocytes, it was shown that p.Arg178Ter behaves almost as a null allele, practically abolishing the protein's sulfate transport activity [14]. The substitution p.Arg279Trp has been found in AO2 mostly in compound heterozygosity with p.Arg178Ter or with another null allele [7] [10] [13] [15], and the p.Arg178Ter + p.Arg279Trp genotype has been identified in almost half of the patients with AO2, as well as in 20% of patients with DTD diagnosed at the Lausanne Molecular Pediatrics laboratory (L. Mittaz-Crettol, personal communication). "
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    ABSTRACT: Atelosteogenesis type II (AO2) and diastrophic dysplasia (DTD) are two recessively inherited, severe skeletal dysplasias caused by mutations in the SLC26A2 gene. AO2 is an invariably lethal condition, while DTD patients may reach adult life, although both diseases have overlapping diagnostic features. Here we report a patient with an intermediate phenotype between AO2 and DTD and present the successful application of preimplantation genetic diagnosis (PGD) in this situation. Sequencing of SLC26A2 alleles in the infant identified two compound heterozygous mutations, p.Arg178Ter and p.Arg279Trp, of paternal and maternal origin, respectively. At request from the parents, PGD was developed by haplotype mapping of parental SLC26A2 alleles in eleven five-day embryos. Transference to the mother was attempted twice, finally resulting in pregnancy and delivery of a healthy baby. This exemplifies the utility of PGD for inherited lethal conditions with a significant risk of recurrence, and highlights the importance of accurate diagnosis of skeletal dysplasias with prenatal manifestation.
    Open Journal of Obstetrics and Gynecology 05/2014; 4(7):399-404. DOI:10.4236/ojog.2014.47060
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    • "gene with sulfate uptake by the fibroblasts and the ultimate phenotype in patients. To date, such a relationship has not been established [Rossi et al., 1996; Superti-Furga et al., 1996; Mégarbané et al., 1999; Karniski, 2001]. "
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    ABSTRACT: The osteochondrodysplasias represent a heterogeneous group of cartilage and bone diseases. Among these, achondrogenesis 1B, atelosteogenesis type II, diastrophic dysplasia, and autosomal recessive multiple epiphyseal dysplasia are caused by mutations in the solute carrier family 26 (sulfate transporter), member 2 gene (SLC26A2). This group of osteochondrodysplasias shows a continuous spectrum of clinical variability and shares many features in common. Usually, it is difficult to distinguish clinically among these patients. To date, several efforts have been made to correlate mutations in the SLC26A2 gene with phenotypic severity in the patients. We report on a Mexican girl with diastrophic dysplasia presenting some unusual clinical and radiographic features that are usually observed in atelosteogenesis type II. Molecular analysis of the SLC26A2 gene in this patient showed compound heterozygosity for the R178X and R279W mutations. In this patient, the combination of a mild and a severe mutation has apparently led to an intermediate or transitional clinical picture, showing an apparent genotype-phenotype correlation.
    American Journal of Medical Genetics Part A 09/2004; 129A(2):190-2. DOI:10.1002/ajmg.a.30149 · 2.05 Impact Factor
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    • "This assay is solid and reproducible (within 10%), and we use it routinely for diagnostic purposes. Sulfate incorporation was most severely impaired in ACGIB and less severely in DTD, according to the less severe clinical phenotype, with AO2 lying in between with an overlap with DTD, as has been observed clinically (Rossi et al., 1996b). Variability was greatest in DTD, possibly reflecting variations in the residual activity of the sulfate transporter or different activity of other transporters or pathways which can provide sulfate for PG sulfation, or yet other factors. "
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    ABSTRACT: Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene have been associated with a family of chondrodysplasias that includes diastrophic dysplasia (DTD), atelosteogenesis type 2 (AO2) and the lethal condition achondrogenesis type 1B (ACG1B). There is a correlation between the nature of the mutations and the clinical phenotype, but our understanding of the pathophysiology of the disorder, which involves defective sulfation of cartilage proteoglycans, is far from complete. To evaluate the degree of proteoglycan undersulfation in vivo, we have extracted chondroitin sulfate proteoglycans from cartilage of twelve patients with sulfate transporter chondrodysplasias and analyzed their disaccharide composition by HPLC after digestion with chondroitinase ABC. The amount of non-sulfated disaccharide was elevated in patients' samples (controls, 5.5% ± 2.8 (n = 10); patients, 11% to 77%), the highest amount being present in ACG1B patients, indicating that undersulfation of chondroitin sulfate proteoglycans occurs in cartilage in vivo and is correlated with the clinical severity. To investigate further the biochemical mechanisms responsible for the translation of genotype to phenotype, we have studied fibroblast cultures of patients with DTD, AO2 and ACG1B, and controls, by double-labelling with [35S]sulfate and [3H]glucosamine. The incorporation of extracellular sulfate, estimated by the 35S/3H ratio in proteoglycans, was reduced in all patients' cells, with ACG1B cells showing the lowest values. However, disaccharide analysis of chondroitin sulfate proteoglycans showed that these were normally sulfated or only moderately undersulfated; marked undersulfation was observed only after addition of the artificial glycosaminoglycan-chain initiator, β-D-xyloside, to the culture medium. These results suggest that, while utilization of extracellular sulfate is impaired, fibroblasts can replenish their intracellular sulfate pool by oxidizing sulfur-containing compounds (such as cysteine) and thus partially rescue PG sulfation under basal conditions. This rescue pathway becomes insufficient when GAG synthesis rate is stimulated by β-D-xyloside. These findings may explain why phenotypic consequences of DTDST mutations are restricted to cartilage, a tissue with high GAG synthesis rate and poor vascular supply, and imply that pharmacological therapy aimed at restoring the intracellular sulfate pool might improve PG sulfation in DTD and related disorders.
    Matrix Biology 11/1998; 17(5-17):361-369. DOI:10.1016/S0945-053X(98)90088-9 · 5.07 Impact Factor
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