Phenotypic and genotypic overlap between atelosteogenesis type 2 and diastrophic dysplasia

University of Pavia, Ticinum, Lombardy, Italy
Human Genetics (Impact Factor: 4.82). 01/1997; 98(6):657-61. DOI: 10.1007/s004390050279
Source: PubMed


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.
    Full-text · Article · May 2014 · Open Journal of Obstetrics and Gynecology
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    • "Disruption of human SLC26A2 causes a spectrum of osteochondrodysplasias, including achondrogenesis type 1B (OMIM#600972) [21], atelosteogenesis type II (OMIM#256050) [22], recessive multiple epiphyseal dysplasia (OMIM#226900) [23], [24], and diastrophic dysplasia (OMIM#222600) [25]. The shared features of these disorders are growth retardation, disproportionately short limbs, narrow, flattened chest, rounded abdomen, clubfoot, cleft palate, and “hitchhiker” thumbs ( "
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    ABSTRACT: A crippling dwarfism was first described in the Miniature Poodle in Great Britain in 1956. Here, we resolve the genetic basis of this recessively inherited disorder. A case-control analysis (8∶8) of genotype data from 173 k SNPs revealed a single associated locus on CFA14 (P(raw) <10(-8)). All affected dogs were homozygous for an ancestral haplotype consistent with a founder effect and an identical-by-descent mutation. Systematic failure of nine, nearly contiguous SNPs, was observed solely in affected dogs, suggesting a deletion was the causal mutation. A 130-kb deletion was confirmed both by fluorescence in situ hybridization (FISH) analysis and by cloning the physical breakpoints. The mutation was perfectly associated in all cases and obligate heterozygotes. The deletion ablated all but the first exon of SLC13A1, a sodium/sulfate symporter responsible for regulating serum levels of inorganic sulfate. Our results corroborate earlier findings from an Slc13a1 mouse knockout, which resulted in hyposulfatemia and syndromic defects. Interestingly, the metabolic disorder in Miniature Poodles appears to share more clinical signs with a spectrum of human disorders caused by SLC26A2 than with the mouse Slc13a1 model. SLC26A2 is the primary sodium-independent sulfate transporter in cartilage and bone and is important for the sulfation of proteoglycans such as aggregan. We propose that disruption of SLC13A1 in the dog similarly causes undersulfation of proteoglycans in the extracellular matrix (ECM), which impacts the conversion of cartilage to bone. A co-dominant DNA test of the deletion was developed to enable breeders to avoid producing affected dogs and to selectively eliminate the mutation from the gene pool.
    Full-text · Article · Dec 2012 · PLoS ONE
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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.
    Full-text · Article · Sep 2004 · American Journal of Medical Genetics Part A
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