A family of chondrodysplasias caused by mutations in the diastrophic dysplasia sulfate transporter gene and associated with impaired sulfation of proteoglycans.
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Anion Transport Proteins↗
Biomedical subjects
D H Cohn
Publications and source records attributed to D H Cohn.
Achondrogenesis type IB is caused by mutations in the diastrophic dysplasia sulphate transporter gene.
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Achondroplasia↗
Atelosteogenesis type II is caused by mutations in the diastrophic dysplasia sulfate-transporter gene (DTDST): evidence for a phenotypic series involving three chondrodysplasias.
Atelosteogenesis type II (AO II) is a neonatally lethal chondrodysplasia whose clinical and histological characteristics resemble those of another chondrodysplasia, the much less severe diastrophic dysplasia (DTD). The similarity suggests a shared pathogenesis involving lesions in the same biochemical pathway and perhaps the same gene. DTD is caused by mutations in the recently identified diastrophic dysplasia sulfate-transporter gene (DTDST). Here, we report that AOII patients also have DTDST mutations, which lead to defective uptake of inorganic sulfate and insufficient sulfation of macromolecules by patient mesenchymal cells in vitro. Together with our recent observation that a third even more severe chondrodysplasia, achondrogenesis type IB, is also caused by mutations in DTDST, these results demonstrate a phenotypic series of three chondrodysplasias of increasing severity caused by lesions in a single sulfate-transporter gene. The severity of the phenotype appears to be correlated with the predicted effect of the mutations on the residual activity of the DTDST protein.
Anion Transport Proteins↗
High-resolution genetic and physical mapping of multiple epiphyseal dysplasia and pseudoachondroplasia mutations at chromosome 19p13.1-p12.
Multiple epiphyseal dysplasia (MED) and pseudoachondroplasia (PSACH) are autosomal dominant chondrodysplasias that have similar phenotypes at both clinical and cytological levels. With the recent mapping of PSACH and one form of MED (EDM1) to the pericentromeric region of chromosome 19, it is likely that the disease mutations are allelic. D19S212 and D19S215, genetic markers flanking the EDM1/PSACH locus, have been localized in a chromosome 19 physical map consisting of cosmid contigs ordered by high-resolution FISH. These two markers define an interval of approximately 3.1 Mb at the 19p13.1-p12 boundary. With as many as five informative crossovers within the D19S212-D19S215 interval in one family with EDM1 and one family with a mild form of PSACH, recombination mapping at greater resolution was undertaken. From cosmid contigs physically mapped within the D19S212-D19S215 interval, four new dinucleotide repeat polymorphisms have been identified. Analysis of recombinant haplotypes in the two families has narrowed the possible location of the EDM1/PSACH gene to an interval of approximately 600 kb.
Base Sequence↗
Thanatophoric dysplasia (types I and II) caused by distinct mutations in fibroblast growth factor receptor 3.
Thanatophoric dysplasia (TD), the most common neonatal lethal skeletal dysplasia, affects one out of 20,000 live births. Affected individuals display features similar to those seen in homozygous achondroplasia. Mutations causing achondroplasia are in FGFR3, suggesting that mutations in this gene may cause TD. A sporadic mutation causing a Lys650Glu change in the tyrosine kinase domain of FGFR3 was found in 16 of 16 individuals with one type of TD. Of 39 individuals with a second type of TD, 22 had a mutation causing an Arg248Cys change and one had a Ser371Cys substitution, both in the extracellular region of the protein. None of these mutations were found in 50 controls showing that mutations affecting different functional domains of FGFR3 cause different forms of this lethal disorder.
Alleles↗
Dominant mutations in the type II collagen gene, COL2A1, produce spondyloepimetaphyseal dysplasia, Strudwick type.
The chondrodysplasias are a heterogeneous group of disorders characterized by abnormal growth or development of cartilage. Current classification is based on mode of inheritance as well as clinical, histologic, and/or radiographic features. A clinical spectrum of chondrodysplasia phenotypes, ranging from mild to perinatal lethal, is due to defects in the gene for type II collagen, COL2A1. This spectrum includes Stickler syndrome, Kniest dysplasia, spondyloepiphyseal dysplasia congenita (SEDC), achondrogenesis type II, and hypochondrogenesis. Individuals affected with these disorders exhibit abnormalities of the growth plate, nucleus pulposus, and vitreous humor, which are tissues that contain type II collagen. The Strudwick type of spondyloepimetaphyseal dysplasia (SEMD) is characterized by disproportionate short stature, pectus carinatum, and scoliosis, as well as dappled metaphyses (which are not seen in SEDC). The phenotype was first described by Murdoch and Walker in 1969, and a series of 14 patients was later reported by Anderson et al. The observation of two affected sibs born to unaffected parents led to the classification of SEMD Strudwick as an autosomal recessive disorder. We now describe the biochemical characterization of defects in alpha 1(II) collagen in three unrelated individuals with SEMD Strudwick, each of which is due to heterozygosity for a unique mutation in COL2A1. Our data support the hypothesis that some cases, if not all cases, of this distinctive chondrodysplasia result from dominant mutations in COL2A1, thus expanding the clinical spectrum of phenotypes associated with this gene.
Adult↗
Another mutation that results in the substitution of an unpaired cysteine residue in the extracellular domain of FGFR3 in thanatophoric dysplasia type I.
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Amino Acid Sequence↗
A radiographic, morphologic, biochemical and molecular analysis of a case of achondrogenesis type II resulting from substitution for a glycine residue (Gly691-->Arg) in the type II collagen trimer.
The type II collagenopathies form a continuous spectrum of clinical severity, ranging from lethal achondrogenesis type II and hypochondrogenesis, through spondyloepiphyseal dysplasia, spondyloepimetaphyseal dysplasia and Kniest dysplasia to the Stickler syndrome and familial precocious osteoarthropathy at the mildest end of the spectrum. We have carried out a radiographic, morphologic, biochemical and molecular study in a case of achondrogenesis type II. Electron micrographs showed inclusion bodies of dilated rough endoplasmic reticulum in the chondrocytes and the presence of sparse collagen fibers in the cartilage matrix. Protein analysis of collagen from cartilage indicated posttranslational overmodification of the major cyanogen bromide peptides, and suggested a mutation near the carboxyl terminus of the type II collagen molecule. Analysis at the DNA level demonstrated that the phenotype was produced by a single base change (G-->C) that resulted in the substitution of glycine691 by arginine in the type II collagen triple helical domain. We confirm previous observations in three cases of hypochondrogenesis that glycine substitutions in the alpha 1(II) chain can result in a phenotype at the most severe end of the type II collagenopathy spectrum.
Abortion, Induced↗
An RNA-splicing mutation (G+5IVS20) in the type II collagen gene (COL2A1) in a family with spondyloepiphyseal dysplasia congenita.
Defects in type II collagen have been demonstrated in a phenotypic continuum of chondrodysplasias that includes achondrogenesis II, hypochondrogenesis, spondyloepiphyseal dysplasia congenita (SEDC), Kniest dysplasia, and Stickler syndrome. We have determined that cartilage from a terminated fetus with an inherited form of SEDC contained both normal alpha 1(II) collagen chains and chains that lacked amino acids 256-273 of the triple-helical domain. PCR amplification of this region of COL2A1, from genomic DNA, yielded products of normal size, while amplification of cDNA yielded a normal sized species and a shorter fragment missing exon 20. Sequence analysis of genomic DNA from the fetus revealed a G-->T transversion at position +5 of intron 20; the affected father was also heterozygous for the mutation. Allele-specific PCR and heteroduplex analysis of a VNTR in COL2A1 independently confirmed the unaffected status of a fetus in a subsequent pregnancy. Thermodynamic calculations suggest that the mutation prevents normal splicing of exon 20 by interfering with binding of U1 small-nuclear RNA to pre-mRNA, thus leading to skipping of exon 20 in transcripts from the mutant allele. Electron micrographs of diseased cartilage showed intracellular inclusion bodies, which were stained by an antibody to alpha 1(II) procollagen. Our findings support the hypothesis that alpha-chain length alterations that preserve the Gly-X-Y repeat motif of the triple helix result in partial intracellular retention of alpha 1(II) procollagen and produce mild to moderate chondrodysplasia phenotypes.
Adult↗
Clinical--molecular correlations in the skeletal dysplasias.
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Child↗
A single amino acid substitution (G103D) in the type II collagen triple helix produces Kniest dysplasia.
Kniest dysplasia is a moderately severe chondrodysplasia phenotype that results from mutations in the gene for type II collagen, COL2A1. Characteristics of the disorder include a short trunk and extremities, mid-face hypoplasia, cleft palate, myopia, retinal detachment, and hearing loss. Recently, deletions of all or part of exon 12 have been identified in individuals with Kniest dysplasia, suggesting that mutations within this region of the protein may primarily result in the Kniest dysplasia phenotype. We used SSCP to analyze an amplified genomic DNA fragment containing exon 12 from seven individuals with Kniest dysplasia. An abnormality was identified in one patient. DNA sequence analysis demonstrated that the patient was heterozygous for a G to A transition that implied substitution of glycine103 of the triple helical domain by aspartate. The mutation was not observed in DNA from either of the clinically unaffected parents of the proband. Protein microsequencing demonstrated expression of the abnormal allele in cartilage. These data demonstrate that point mutations which result in single amino acid substitutions can produce Kniest dysplasia and further support the hypothesis that alteration of a domain, which includes the region encoded by exon 12, in the type II collagen protein leads to this disorder.
Amino Acid Sequence↗
Expression, in cartilage, of a 7-amino-acid deletion in type II collagen from two unrelated individuals with Kniest dysplasia.
Kniest dysplasia is a heritable chondrodysplasia that severely affects skeletal growth. Recent evidence suggests that the etiology is based on mutations in COL2A1, the gene for collagen type II. We report the detection and partial characterization of an identical defect in type II collagen in two unrelated patients with Kniest dysplasia. Analysis of cyanogen bromide (CB)-digested cartilage samples from both probands by SDS-PAGE revealed an abnormal band for peptide alpha 1(II)CB12. The peptide was purified and digested with endoproteinase Asp-N. Fragments unique to the Kniest tissues were identified by reverse-phase high-pressure liquid chromatography and by sequence analysis. The results established a deletion of amino acids 102-108 of the alpha 1(II) triple-helical domain, which disrupted the (gly-X-Y)n repeat needed for helix formation. This was confirmed by sequence analysis of DNA amplified from both probands, revealing the molecular basis to be a single nucleotide mutation at a CpG dinucleotide (GCG-->GTG) in the codon for alanine 102. The mutation created a new splice donor site, which would account for the absence of the last seven amino acids from the 3' end of exon 12 in alpha 1(II)CB12. Light and electron micrographs of the probands' cartilage showed the perilacunar foamy matrix ("Swiss cheese") characteristic of Kniest dysplasia and chondrocytes containing dilated rough endoplasmic reticulum, which earlier studies had shown were filled with type II procollagen. These two cases strengthen the concept that Kniest dysplasia is based on mutations of COL2A1 and belongs within the broad spectrum of chondrodysplasias caused by type II collagenopathies.
Adult↗
Homology-mediated recombination between type I collagen gene exons results in an internal tandem duplication and lethal osteogenesis imperfecta.
It has been proposed that the structure of the exons that encode the triple helical domain of the fibrillar collagen genes arose by repeated tandem duplication of an ancestral unit exon. Because these exons encode a repeat motif [(Gly-X-Y)n], sequence homology between exons may have driven the recombinational process. We have characterized a tandem duplication mutation within a COL1A1 allele of type I collagen from an infant with the lethal form of osteogenesis imperfecta. The structure of the mutation is consistent with the occurrence of an unequal crossover within a 15 base pair region of sequence identity between exons 14 and 17 of the COL1A1 gene. The recombination produced a new 81 base pair 17/14 hybrid exon and complete duplication of exons 15 and 16. The sequence implies duplication of 60 amino acid residues within the triple helical domain with preservation of the Gly-X-Y repeat. These data suggest that a recombinational mechanism that explains the hypothetical evolutionary process is active in cells, but the lethal effect of this mutation raises questions about the role of these events in creating new structures for polymeric proteins.
Amino Acid Sequence↗
First-trimester prenatal diagnosis of osteogenesis imperfecta type II by DNA analysis and sonography.
Osteogenesis imperfecta type II was diagnosed prenatally by analysis of DNA obtained from chorionic villus sampling (CVS) performed at 12 weeks of gestation in a woman who previously had had an affected child. The father had been shown to be mosaic for a mutation in the gene (COL1A2) which encodes the alpha 2(I) chain of type I collagen. An affected fetus was predicted by detection of the mutation in amplified chorionic villus genomic DNA. Ultrasound examination at 13 weeks 4 days demonstrated femoral deformity and virtual absence of calvarial mineralization. In pregnancies at risk for osteogenesis imperfecta type II, sonographic evidence of skeletal abnormalities may be evident by 13 weeks' gestation.
Adult↗
Heteroduplex analysis can increase the informativeness of PCR-amplified VNTR markers: application using a marker tightly linked to the COL2A1 gene.
Variable number of tandem repeat (VNTR) polymorphisms provide a high degree of informativeness in linkage studies. Whether performed by standard methods or by polymerase chain reaction (PCR), analysis of these markers involves assessment of the length of each allele. VNTR alleles usually differ in the number of tandem repeats. During PCR amplification of a VNTR closely linked to the type II collagen gene (COL2A1), we identified allelic microheterogeneity through the analysis of unique heteroduplexes between amplified strands of the two alleles. In one large pedigree, heteroduplex analysis identified six COL2A1 alleles; standard methods would have identified only three distinct alleles. The identification of these heteroduplexes allowed the determination of the COL2A1 inheritance pattern in the family, which otherwise would have been noninformative.
Alleles↗
Genetic linkage of mild pseudoachondroplasia (PSACH) to markers in the pericentromeric region of chromosome 19.
Pseudoachondroplasia (PSACH) is a dominantly inherited form of short-limb dwarfism characterized by dysplastic changes in the spine, epiphyses, and metaphyses and early onset osteoarthropathy. Chondrocytes from affected individuals accumulate an unusual appearing material in the rough endoplasmic reticulum, which has led to the hypothesis that a structural abnormality in a cartilage-specific protein produces the phenotype. We recently identified a large family with a mild form of pseudoachondroplasia. By genetic linkage to a dinucleotide repeat polymorphic marker (D19S199), we have localized the disease gene to chromosome 19 (maximum lod score of 7.09 at a recombination fraction of 0.03). Analysis of additional markers and recombinants between the linked markers and the phenotype suggests that the disease gene resides within a 6.3-cM interval in the immediate pericentromeric region of the chromosome.
Achondroplasia↗
Linkage of typical pseudoachondroplasia to chromosome 19.
Pseudoachondroplasia (PSACH) is an autosomal dominant dwarfing condition associated with disproportionate short stature, marked joint deformities, and early onset osteoarthritis. Previous linkage studies have excluded linkage to cartilage and noncartilagenous extracellular matrix candidate genes. Here, we report mapping the pseudoachondroplasia gene to chromosome 19. Maximum lod scores of 4.70, 4.15, and 4.86 at theta = 0.00 were found for D19S212, D19S215, and D19S49, respectively. Multipoint analysis suggests the following order: D19S253-D19S199-(D19S212/PSACH/D19S215)-++ +D19S222-D19S49.
Achondroplasia↗
A type X collagen mutation causes Schmid metaphyseal chondrodysplasia.
The expression of type X collagen is restricted to hypertrophic chondrocytes in regions undergoing endochondral ossification, such as growth plates. The precise function of type X collagen is unknown but the tissue-specific expression prompted us to examine the gene in hereditary disorders of cartilage and bone growth (osteochondrodysplasias). We have identified a 13 base pair deletion in one type X collagen allele segregating with autosomal dominant Schmid metaphyseal chondrodysplasia in a large Mormon kindred (lod score = 18.2 at theta = 0). The mutation produces a frameshift which alters the highly conserved C-terminal domain of the alpha 1(X) chain and reduces the length of the polypeptide by nine residues. This mutation may prevent association of the mutant polypeptide during trimer formation, resulting in a decreased amount of normal protein.
Alleles↗