A mutation in the variable repeat region of the aggrecan gene (AGC1) causes a form of spondyloepiphyseal dysplasia associated with severe, premature osteoarthritis.
ABSTRACT: Spondyloepiphyseal dysplasia (SED) encompasses a heterogeneous group of disorders characterized by shortening of the trunk and limbs. The autosomal dominant SED type Kimberley (SEDK) is associated with premature degenerative arthropathy and has been previously mapped in a multigenerational family to a novel locus on 15q26.1. This locus contains the gene AGC1, which encodes aggrecan, the core protein of the most abundant proteoglycan of cartilage. We screened AGC1 for mutations and identified a single-base-pair insertion, within the variable repeat region of exon 12 in affected individuals from the family with SEDK, that introduces a frameshift of 212 amino acids, including 22 cysteine residues, followed by a premature stop codon. This is the first identification of an AGC1 mutation causing a human disorder. This finding extends the spectrum of mutated genes that may cause SED and thus will aid in the molecular delineation of this complex group of conditions.
Project description:We have investigated a family with an autosomal dominant form of spondyloepiphyseal dysplasia (SED) characterised by short stature and severe premature degenerative arthropathy. Previous studies have excluded linkage between this condition and the locus for the type II collagen gene. Here we report the identification of linkage between this disorder and a locus on the long arm of chromosome 15 between markers D15S979 and D15S1004. According to current linkage maps and sequence data, this locus includes that of the aggrecan gene (AGC1). Our linkage data from the SED family show, however, that AGC1 maps to a locus that is proximal to D15S979. This proximal location for AGC1 is further supported by linkage data from a second family with an autosomal recessive form of multiple epiphyseal dysplasia that also maps to the SED locus. In both families AGC1 is therefore excluded as a candidate gene.
Project description:Skeletal dysplasias form a group of skeletal disorders caused by mutations in macromolecules of cartilage and bone. The severity of skeletal dysplasias ranges from precocious arthropathy to perinatal lethality. Although the pathomechanisms of these disorders are generally well defined, the feasibility of repairing established aberrant skeletal tissues that developed in the presence of mutant molecules is currently unknown. Here, we employed a validated mouse model of spondyloepiphyseal dysplasia (SED) that enables temporal control of the production of the R992C (p.R1192C) collagen II mutant that causes this disease. Although in our earlier studies we determined that blocking the expression of this mutant at the early prenatal stages prevents a SED phenotype, the utility of blocking the R992C collagen II at the postnatal stages is not known. Here, by switching off the expression of R992C collagen II at various postnatal stages of skeletal development, we determined that significant improvements of cartilage and bone morphology were achieved only when blocking the production of the mutant molecules was initiated in newborn mice. Our study indicates that future therapies of skeletal dysplasias may require defining a specific time window when interventions should be applied to be successful.
Project description:UNLABELLED:A missense mutation in the mouse Col2a1 gene has been discovered, resulting in a mouse phenotype with similarities to human spondyloepiphyseal dysplasia (SED) congenita. In addition, SED patients have been identified with a similar molecular mutation in human COL2A1. This mouse model offers a useful tool for molecular and biological studies of bone development and pathology. INTRODUCTION:A new mouse autosomal recessive mutation has been discovered and named spondyloepiphyseal dysplasia congenita (gene symbol sedc). MATERIALS AND METHODS:Homozygous sedc mice can be identified at birth by their small size and shortened trunk. Adults have shortened noses, dysplastic vertebrae, femora, and tibias, plus retinoschisis and hearing loss. The mutation was mapped to Chr15, and Col2a1 was identified as a candidate gene. RESULTS:Sequence analyses revealed that the affected gene is Col2a1, which has a missense mutation at exon 48 causing an amino acid change of arginine to cysteine at position 1417. Two human patients with spondyloepiphyseal dysplasia (SED) congenita have been reported with the same amino acid substitution at position 789 in the human COL2A1 gene. CONCLUSIONS:Thus, sedc/sedc mice provide a valuable model of human SED congenita with molecular and phenotypic homology. Further biochemical analyses, molecular modeling, and cell culture studies using sedc/sedc mice could provide insight into mechanisms of skeletal development dependent on Col2a1 and its role in fibril formation and cartilage template organization.
Project description:Spondyloepiphyseal dysplasia (SED) comprises a heterogeneous group of skeletal dysplasias that primarily affect the epiphyses and vertebral bodies. Patients affected by SED usually exhibit short stature and experience early development of degenerative osteoarthritis. SED is subdivided into congenita and tarda forms according to the age at onset and clinical severity, and further subdivided into genetically different forms according to the mode of inheritance and the gene involved. We report a 14-yr-old Korean male who presented with a disproportionately short stature and a short trunk. A pedigree analysis of 3 generations with 6 affected persons revealed an X-linked recessive mode of inheritance. Mutation analysis of the TRAPPC2 (previously called SEDL) gene, the only gene associated with X-linked spondyloepiphyseal dysplasia tarda (X-linked SEDT; MIM 313400), was performed, and a splice-donor site mutation in intron 3 of the TRAPPC2 gene (c.93+5G>A) was identified in the proband and in his unaffected mother (a heterozygote). This mutation is one of the 2 most frequent mutations reported in the medical literature, and is known to result in exon 3 skipping. This is the first report of a genetically confirmed X-linked SEDT case in Korea and highlights the importance of recognizing the mode of inheritance in the diagnosis of X-linked SEDT.
Project description:Progressive pseudorheumatoid dysplasia (PPRD) is a rare, autosomal-recessive condition characterized by mild spondyloepiphyseal dysplasia (SED) and severe, progressive, early-onset arthritis due to WISP3 mutations. SED, Stanescu type, is a vaguely delineated autosomal-dominant dysplasia of unknown genetic etiology. Here, we report three individuals from two unrelated families with radiological features similar to PPRD and SED, Stanescu type who share the same novel COL2A1 variant and were matched following discussion at an academic conference. In the first family, we performed whole-exome sequencing on three family members, two of whom have a PPRD-like phenotype, and identified a heterozygous variant (c.619G>A, p.Gly207Arg) in both affected individuals. Independently, targeted sequencing of the COL2A1 gene in an unrelated proband with a similar phenotype identified the same heterozygous variant. We suggest that the p.Gly207Arg variant causes a distinct type II collagenopathy with features of PPRD and SED, Stanescu type.
Project description:Introduction:X-linked spondyloepiphyseal dysplasia tarda(SEDT) is a type of shorttrunk skeletal dysplasia, occurring in males due to mutation in TRAPPC2 gene. Case Report:We describe a large Indian family with multiple males affected with X-linked SEDT. The affected individuals presented with disproportionate short stature, short trunk, and barrel-shaped chest. Elder sibs aged 26 years and 31 years had back and hip pain. Premature osteoarthritis was seen requiring hip replacement surgery in one sib. The known pathogenic nonsense mutation c.209G>A (p.W70X) was identified in TRAPPC2 gene. This is the first mutation proven Indian kindred with X-linked SEDT. Conclusion:Knowledge of molecular basis is essential to provide definitive diagnosis, accurate counseling, and prenatal diagnosis or early postnatal diagnosis for this rare condition.
Project description:Schimke immunoosseous dysplasia (SIOD) is an autosomal recessive multisystem disorder characterized by prominent spondyloepiphyseal dysplasia, T cell deficiency, and focal segmental glomerulosclerosis. Biallelic mutations in swi/snf-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1 (SMARCAL1) are the only identified cause of SIOD, but approximately half of patients referred for molecular studies do not have detectable mutations in SMARCAL1. We hypothesized that skeletal features distinguish between those with or without SMARCAL1 mutations. Therefore, we analyzed the skeletal radiographs of 22 patients with and 11 without detectable SMARCAL1 mutations. We found that patients with SMARCAL1 mutations have a spondyloepiphyseal dysplasia (SED) essentially limited to the spine, pelvis, capital femoral epiphyses, and possibly the sella turcica, whereas the hands and other long bones are basically normal. Additionally, we found that several of the adolescent and young adult patients developed osteoporosis and coxarthrosis. Of the 11 patients without detectable SMARCAL1 mutations, seven had a SED indistinguishable from patients with SMARCAL1 mutations. We conclude therefore that SED is a feature of patients with SMARCAL1 mutations and that skeletal features do not distinguish who of those with SED have SMARCAL1 mutations.
Project description:The X-linked form of spondyloepiphyseal dysplasia tarda (SEDL), a radiologically distinct skeletal dysplasia affecting the vertebrae and epiphyses, is caused by mutations in the SEDL gene. To characterize the molecular basis for SEDL, we have identified the spectrum of SEDL mutations in 30 of 36 unrelated cases of X-linked SEDL ascertained from different ethnic populations. Twenty-one different disease-associated mutations now have been identified throughout the SEDL gene. These include nonsense mutations in exons 4 and 5, missense mutations in exons 4 and 6, small (2-7 bp) and large (>1 kb) deletions, insertions, and putative splicing errors, with one splicing error due to a complex deletion/insertion mutation. Eight different frameshift mutations lead to a premature termination of translation and account for >43% (13/30) of SEDL cases, with half of these (7/13) being due to dinucleotide deletions. Altogether, deletions account for 57% (17/30) of all known SEDL mutations. Four recurrent mutations (IVS3+5G-->A, 157-158delAT, 191-192delTG, and 271-275delCAAGA) account for 43% (13/30) of confirmed SEDL cases. The results of haplotype analyses and the diverse ethnic origins of patients support recurrent mutations. Two patients with large deletions of SEDL exons were found, one with childhood onset of painful complications, the other relatively free of additional symptoms. However, we could not establish a clear genotype/phenotype correlation and therefore conclude that the complete unaltered SEDL-gene product is essential for normal bone growth. Molecular diagnosis can now be offered for presymptomatic testing of this disorder. Appropriate lifestyle decisions and, eventually, perhaps, specific SEDL therapies may ameliorate the prognosis of premature osteoarthritis and the need for hip arthroplasty.
Project description:Spondyloepiphyseal dysplasia congenita (SEDC) is an autosomal dominant disorder, characterized by disproportionate dwarfism with short spine, short neck associated with variable degrees of coxa vara. Cervical cord compression is the most hazardous skeletal deformity in patients with SEDC which requires special attention and management.Ten patients with the clinical and the radiographic phenotypes of spondyloepiphyseal dysplasia congenita have been recognized and the genotype was compatible with single base substitutions, deletions or duplication of part of the COL2A1 gene (6 patients out of ten have been sequenced). Cervical spine radiographs showed apparent atlantoaxial instability in correlation with odontoid hypoplasia or os-odontoideum.Instability of 8?mm or more and or the presence of symptoms of myelopathy were the main indications for surgery. Posterior cervical fusion from the occiput or C1-3, decompression of C1-2 and application of autorib transfer followed by halo vest immobilization have been applied accordingly.Orthopedic management of children with spondyloepiphyseal dysplasia congenita (SEDC) should begin with the cervical spine to avoid serious neurological deficits and or mortality.
Project description:Spondyloepiphyseal dysplasia congenita (SEDC, OMIM #183900) is one of the type II collagenopathies caused by a heterozygous mutation in the COL2A1 gene. Although typical SEDC shows delay of pubic bone ossification on radiographs, atypical SEDC exists without this finding. We identified an atypical SEDC patient with a novel missense mutation in the C-propeptide region of COL2A1. This case suggests that a COL2A1 C-propeptide mutation can cause atypical SEDC.