Phenotypic and genotypic overlap between atelosteogenesis type 2 and diastrophic dysplasia

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.

Slc26a9 Is Inhibited by the R-region of the Cystic Fibrosis Transmembrane Conductance Regulator via the STAS Domain

“…(5,(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41). Mouse studies have revealed additional roles for these Slc26 proteins in mammalian physiology: deafness, goiter, and acidosis (Slc26a4, pendrin) (42-44), cochlear motor protein (Slc26a5, prestin) (45)(46)(47), proximal tubule NaCl absorption, nephrolithiasis, and intestinal HCO 3 Ϫ secretion (Slc26a6, Pat-1, CFEX) (8, 48 -52), sperm motility (Slc26a8, Tat-1) (53), and gastric acid secretion (Slc26a9) (14).…”

Mechanisms in Protein O-Glycan Biosynthesis and Clinical and Molecular Aspects of Protein O-Glycan Biosynthesis Defects: A Review

“…Phenotypically, AO-II is the severe variant of DTD. In addition to the clinical features described for DTD, AO-II is characterized by severe and progressive kyphosis, horizontal sacrum, and a gap between the first and the second toes (116 ) …”

Identification of the Finnish founder mutation for diastrophic dysplasia (DTD)

“…Both these mutations have been previously identified in DTDST-related disorders R279W in DTD and AOII and V340del in ACG1B. [3][4][5][6][7]13 In the one family carrying no copies of DTDST Fin , the patient was a compound heterozygote for R279W/V340del.…”

“…DTDST mutations thus give rise to a clinical spectrum, with compound heterozygosity and mutational overlap observed: several mutations have been detected in two or three of the conditions. [3][4][5][6][7] The severity of the phenotype appears to correlate with residual DTDST function, although additional factors can also influence expression as illustrated by intrafamilial phenotypic variability. 8,9 Despite extensive characterization of DTDST mutations, we had previously been unable to identify the major founder mutation accounting for the high prevalence of DTD in the Finnish population.…”