Schmid Metaphyseal Chondrodysplasia Research Articles

Collagen type X expression and chondrocyte hypertrophic differentiation during OA and OS development.

Chondrocyte hypertrophy and the expression of its specific marker, the collagen type X gene (COL10A1), constitute key terminal differentiation stages during endochondral ossification in long bone development. Mutations in the COL10A1 gene are known to cause schmid type metaphyseal chondrodysplasia (SMCD) and spondyloepiphyseal dyschondrodysplasia (SMD). Moreover, abnormal COL10A1 expression and aberrant chondrocyte hypertrophy are strongly correlated with skeletal diseases, notably osteoarthritis (OA) and osteosarcoma (OS). Throughout the progression of OA, articular chondrocytes undergo substantial changes in gene expression and phenotype, including a transition to a hypertrophic-like state characterized by the expression of collagen type X, matrix metalloproteinase-13, and alkaline phosphatase. This state is similar to the process of endochondral ossification during cartilage development. OS, the most common pediatric bone cancer, exhibits characteristics of abnormal bone formation alongside the presence of tumor tissue containing cartilaginous components. This observation suggests a potential role for chondrogenesis in the development of OS. A deeper understanding of the shifts in collagen X expression and chondrocyte hypertrophy phenotypes in OA or OS may offer novel insights into their pathogenesis, thereby paving the way for potential therapeutic interventions. This review systematically summarizes the findings from multiple OA models (e.g., transgenic, surgically-induced, mechanically-loaded, and chemically-induced OA models), with a particular focus on their chondrogenic and/or hypertrophic phenotypes and possible signaling pathways. The OS phenotypes and pathogenesis in relation to chondrogenesis, collagen X expression, chondrocyte (hypertrophic) differentiation, and their regulatory mechanisms were also discussed. Together, this review provides novel insights into OA and OS therapeutics, possibly by intervening the process of abnormal endochondral-like pathway with altered collagen type X expression.

A rare case of SCHMID metaphyseal chondrodysplasia associated with hypothyroidism,growth hormone deficiency and celiac disease: case report.

The authors present a rare case of 4-year-2-month-old boy referred to our Unit for harmonious short stature, he had a waddling gait, subtle micromelia, and hyperlordosis, no special facies. The skeletal scan made the diagnosis of SCHMID metaphyseal chondrodysplasia. The first laboratory workup showed elevated thyroid stimulating hormone and anti-tissue transglutaminase immunoglobulin A. The duodenal biopsies confirmed the diagnosis of coeliac disease. Treatment of levothyroxine was initiated with a gluten-free diet .6 years later, his re-evaluation showed a low insulin-like growth factor 1 and low growth hormone peaks confirming the diagnosis of growth hormone deficiency, Growth hormone therapy was initiated with an adjusted dose of levothyroxine. Other causes of short stature should not be missed when diagnosing chondrodysplasia, and further investigations should be carried out to detect other concomitant disorders since metaphyseal chondrodysplasia is a rare cause for short stature while hypothyroidism and coeliac disease are relatively common.

Clinical and molecular genetic analysis of a child with Schmid type metaphyseal chondrodysplasia

To analyze the clinical features and genotype of a child with Schmid type metaphyseal chondrodysplasia. Clinical data of the child and her parents was collected. The child was subjected to high-throughput sequencing, and candidate variant was verified by Sanger sequencing of her family members. Whole exome sequencing revealed that the child has harbored a heterozygous c.1772G>A (p.C591Y) variant of the COL10A1 gene, which was not found in either of her parents. The variant was not found in the HGMD and ClinVar databases, and was rated as likely pathogenic based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). The heterozygous c.1772G>A (p.C591Y) variant of the COL10A1 gene probably underlay the Schmid type metaphyseal chondrodysplasia in this child. Genetic testing has facilitated the diagnosis and provided a basis for genetic counselling and prenatal diagnosis for this family. Above finding has also enriched the mutational spectrum of the COL10A1 gene.

Natural history and genetic spectrum of the Turkish metaphyseal dysplasia cohort, including rare types caused by biallelic COL10A1, COL2A1, and LBR variants.

Metaphyseal chondrodysplasias are a heterogeneous group of diseases characterized by short and bowed long bones and metaphyseal abnormality. The aim of this study is to investigate the genetic etiology and prognostic findings in patients with metaphyseal dysplasia. Twenty-four Turkish patients were included in this study and 13 of them were followed for 2-21years. COL10A1, RMRP sequencing and whole exome sequencing were performed. Results: Seven heterozygous pathogenic variants in COL10A1 were detected in 17 patients with Schmid type metaphyseal chondrodysplasia(MCDS). The phenotype was more severe in patients with heterozygous missense variants (one in signal peptide domain at the N-terminus of the protein, the other, class-1 group mutation at NC1 domain) compared to the patients with truncating variants. Short stature and coxa vara deformity appeared after 3 and 5years of age, respectively, while large femoral head resolved after the age of 13years in MCDS group. Interestingly, one patient with severe phenotype also had a biallelic missense variant in NC1 domain of COL10A1. Three patients with biallelic mutations in RMRP had prenatal onset short stature with short limb, and typical findings of cartilage hair hypoplasia (CHH). While immunodeficiency or recurrent infections were not observed, resistant congenital anemia was detected in one. Biallelic mutation in LBR was described in a patient with prenatal onset short stature, short and curved limb and metaphyseal abnormalities. Unlike previously reported patients, this patient had ectodermal findings, similar to CHH. A biallelic COL2A1 mutation was also found in the patient with lower limb deformities and metaphyseal involvement without vertebral and epiphyseal changes. Long-term clinical characteristics are presented in a metaphyseal dysplasia cohort, including rare types caused by biallelic COL10A1, COL2A1, and LBR variants. We also point out that the domains where mutations on COL10A1 take place are important in the genotype-phenotype relationship.

Abstract #1178966: A Rare Case of Idiopathic Osteoporosis with COL10A1 and COL27A1 Genetic Mutations in a Premenopausal Woman

The association between bone mineral density (BMD) and fracture differs in premenopausal women when compared to the postmenopausal women. Irrespective of the BMD, any fragility fracture in those aged 20-50 requires evaluation for secondary causes of osteoporosis. In the absence of secondary causes, idiopathic osteoporosis (IOP) is considered. We present a case of a premenopausal woman with IOP whose mutational analysis revealed variants in COL10A1 and COL27A1. These genetic mutations are found in Schmid-type metaphyseal chondrodysplasia (SMCD) and Steel syndrome, respectively. To our knowledge, this is the first case report establishing a linkage between these specific mutations and IOP. A 36-year-old Hispanic woman with a history of fragility fracture of the lumbar spine at age 23 was referred to Endocrinology for further evaluation. Dual-energy x-ray absorptiometry (DEXA) reported a Z-score of -3.0 in L1-L4, consistent with osteoporosis of the lumbar spine. A careful history, physical examination, and laboratory evaluation ruled out secondary causes of osteoporosis. In the interim, the patient presented a recurrent fragility fracture of the left proximal humerus requiring surgical intervention where bone marrow (BM) was obtained for cytology. BM cytology was found normocellular without increase in blasts or lymphocytes. Notably, the mutational analysis revealed heterozygous variants of uncertain significance (VUS) in COL10A1 [variant c682 c >T (p.Pro228Ser)] and COL27A1 [variant c.1814 c >T (p.Thr 6605 Met)]. Whole exome sequencing was not able to be performed due to insurance issues. The most common secondary causes of premenopausal bone loss include estrogen deficiency as seen in hypogonadism, drug exposure such as glucocorticoids, malabsorption disorders like celiac disease, hyperthyroidism, hypercalciuria, hyperparathyroidism, and disturbances in calcium and vitamin D metabolism. Osteoporosis with no known secondary causes is known as IOP. IOP is a disorder with multiple proposed mechanisms including impairment in growth hormone and insulin like growth factor axis, osteoblast dysfunction, and genetic mutations. Mutational analysis in selected IOP cases, have shown pathogenic variants and VUS in LRP5, LRP6, COL1A1, COL1A2, PLS3, WNT1, DKK1, FKBP10, HGD, SLC34A3. Our patient was found with heterozygous VUS in COL10A1 and COL27A1. These genetic mutations are found in (SMCD) and Steel syndrome, respectively. These rare osteochondrodysplasias, more commonly found in childhood, are associated with skeletal abnormalities including scoliosis, congenital hip dislocations, short stature, and characteristic facial features. More importantly, COL10A1 encodes the alpha 1 chain of collagen type X which is involved in growth plate function, and COL27A1 gene encodes a member of the fibrillar collagen family involved in the calcification of cartilage and the transition of cartilage to bone. To our knowledge, COL10A1 and COL27A1 mutations have not been yet associated as primary causes of IOP. We report this case aiming for further research to identify additional genetic etiologies of IOP.

A Missense Mutation in COL10A1 Gene in a Pakistani Consanguineous Family with Schmid Type Metaphyseal Chondrodysplasia

A Missense Mutation in COL10A1 Gene in a Pakistani Consanguineous Family with Schmid Type Metaphyseal Chondrodysplasia

Identification of a novel COL10A1: c.1952 G>T variant in a family with Schmid metaphyseal chondrodysplasia and development of a noninvasive prenatal testing method.

BackgroundThe collagen alpha‐1(X) chain gene (COL10A1) is a known causative gene for Schmid metaphyseal chondrodysplasia (SMCD). This study clinically examined a Chinese family (n = 42) for SMCD and inheritance pattern. Fifteen individuals were diagnosed with SMCD based on characteristic skeletal phenotypes with autosomal dominant inheritance mode.MethodsFour clinically diagnosed patients and three healthy relatives were selected for subsequent genetic tests. Trio‐whole exome sequencing (Trio‐WES) followed by Sanger sequencing and familial co‐segregation analysis were performed to identify SMCD‐associated variants.Results COL10A1 (NM_000493.4):c.1952 G>T(p.Trp651Leu) variant was detected only in the four patients and not in the three healthy relatives. The variant was evaluated as “likely pathogenic” according to the American College of Medical Genetics and Genomics variation classification guidelines with evidence of PM2, PM5, PP1, and PP3. To test the presence of the target variant in proband's fetal offspring, we developed a noninvasive prenatal testing method by extracting cell‐free fetal DNA in maternal plasma followed by high‐depth sequencing. The variant was also detected in the fetus and later confirmed by amniocentesis.ConclusionWe identified a new disease‐causing variant in COL10A1. Cell‐free fetal DNA in maternal peripheral blood can be used as the rapid and noninvasive prenatal diagnostic method to detect the pathogenic/or likely pathogenic variant.

A collagen10a1 mutation disrupts cell polarity and causes skeletal defects in a medaka model for Schmid Metaphyseal Chondrodysplasia

A collagen10a1 mutation disrupts cell polarity and causes skeletal defects in a medaka model for Schmid Metaphyseal Chondrodysplasia

Metaphyseal Chondrodysplasia Schmid type - widening the phenotype: Significant variable expression in two familial cases with heterozygous COL10A1 variants

Metaphyseal Chondrodysplasia Schmid Type (SMCD) is a rare dominant form of skeletal dysplasia, caused by heterozygous mutations in the COL10A1 (Collagen Type X alpha 1) gene which codes for α1 chains in type X collagen, and typically results in disproportionate short stature. We report two families with the clinical and radiological diagnosis of SMCD seen in our unit over 4 years. In the first family (A), the proband had a possible pathogenic COL10A1 variant (c.133C>T, p.Pro45Ser). However, his father had the same variant without any obvious signs of SMCD, causing uncertainty whether this mutation was pathogenic. In the second family (B), the proband and her affected father had the same variant. Almost at the same time, a large consanguineous family was reported to have segregation of the variant with SMCD phenotypes in that the homozygosity was related to severer phenotypes and the heterozygosity to milder phenotypes. Hence, we were convinced that the variant was pathogenic. The pathogenic variant (p.Pro45Ser) causes a wide phenotypic spectrum of SMCD and even subclinical features. In this report, we highlight attenuated phenotypes of SMCD, and also discuss the latest therapeutic advances in SMCD and its mechanism of action.

Identification of two novel COL10A1 heterozygous mutations in two Chinese pedigrees with Schmid-type metaphyseal chondrodysplasia

BackgroundSchmid-type metaphyseal chondrodysplasia (MCDS) is an autosomal dominant disorder caused by COL10A1 mutations, which is characterized by short stature, waddling gait, coxa vara and bowing of the long bones. However, descriptions of the expressivity of MCDS are rare.MethodsTwo probands and available family members affected with MCDS were subjected to clinical and radiological examination. Genomic DNA of all affected individuals was subjected to whole-exome sequencing, and candidate mutations were verified by Sanger sequencing in all available family members and in 250 healthy donors. A spatial model of the type X collagen (α1) C-terminal noncollagenous (NC1) domain was further constructed.ResultsWe found that the phenotype of affected family members exhibited incomplete dominance. Mutation analysis indicated that there were two novel heterozygous missense mutations, [c.1765 T > A (p.Phe589Ile)] and [c.1846A > G (p.Lys616Glu)] in the COL10A1 gene in family 1 and 2, respectively. The two novel substitution sites were highly conserved and the mutations were predicted to be deleterious by in silico analysis. Furthermore, protein modeling revealed that the two substitutions were located in the NC1 domain of collagen X (α1), which potentially impacted the trimerization of collagen X (α1) and combination with molecules in the pericellular matrix.ConclusionTwo novel mutations were identified in the present study, which will facilitate diagnosis of MCDS and further expand the spectrum of the COL10A1 mutations associated with MCDS patients. In addition, our research revealed the phenomenon of incomplete dominance in MCDS.

Tibial lenghtening through callus distraction in a patient with Schmid-type metaphyseal chondrodysplasia with a novel COL10A1-mutation

We report on a patient with Schmid-type metaphyseal chondrodysplasia (MCDS) carrying a novel COL10A1 mutation who underwent bilateral tibial lengthening at the age of 16.5 years using the technique described by Ilizarov. The disease-causing mutation Phe554Leu (g. 1660 T>C) represents the most amino terminal mutation within the NC1-domain of collagen type X described in MCDS so far. Failure of consolidation of the anterior distraction callus required secondary conversion to intramedullary nailing 344 days after primary surgery. Length gained was 5 cm (17.2% of tibial length), and healing index was 160 days/cm (46.5 days/percentage). This is the first case of callus distraction reported in a patient carrying a defined collagen X missense mutation. The associated defect in endochondral ossification may represent a central factor leading to the failure of callus consolidation.

Schmid's Type of Metaphyseal Chondrodysplasia: Diagnosis and Management.

There are several types of metaphyseal chondrodysplasia and various clinical types have been differentiated. The Schmid type of metaphyseal chondrodysplasia is the most common. Diffuse metaphyseal flaring, irregularity, and growth plate widening, which are most severe in the knees, are the most striking radiological features of this disease. The Schmid type of metaphyseal dysostosis is characterized by failure of normal mineralization of the zone of provisional calcification, leading to widened physes and enlarged knobby metaphyses, effectively causing shortening of the tubular bones, splaying of the metaphyses, coxa vara, and bow legs. Orthopaedic interventions were primarily performed on the lower extremities. Twelve children (seven girls and five boys) aged 7-10 years were enrolled in this study. Moderate short stature was a uniform feature associated with predominant involvement of the proximal femora and bow legs resulted in the development of angular deformities. A waddling gait was a consequence of coxa vara in eight children. Valgus osteotomy of the proximal femur was planned after physeal closure for the group of children with coxa vara. Hemiepiphysiodesis was performed to re-align the genu varum in three children. Other forms of metaphyseal dysostosis were ruled based on full clinical and radiographic phenotypes, with confirmation through molecular pathology. Mutations in the COL10A1 gene located on chromosome 6q21-q22.3 were confirmed. Re-alignment was accomplished in our group of patients. The most striking clinical features of Schmid metaphyseal chondrodysplasia which appear within the first 2-3 years of life are: moderate short limbs and short stature, a waddling gait, and increasing shortness of stature with age. The Schmid type of metaphyseal chondrodysplasia is a disorder that arises from defective type X collagen, which is typically found in the hypertrophic zone of the physes. Moderate short stature and a waddling gait associated with pain are the most common clinical presentations. Osteotomies to correct bow legs are sometimes combined with lengthening procedures. Recurrence of the deformities with growth is not uncommon; therefore, hemiepiphysiodesis or stapling might be indicated in some cases.

Identification of key genes associated with Schmid-type metaphyseal chondrodysplasia based on microarray data.

This study aimed to gain a better understanding of the molecular circuitry of Schmid-type metaphyseal chondrodysplasia (SMCD), and to identify more potential genes associated with the pathogenesis of SMCD. Microarray data from GSE72261 were downloaded from the NCBI GEO database, including collagen X p.Asn617Lys knock-in mutation (ColXN617K), ablated XBP1 activity (Xbp1CartΔEx2), compound mutant (C/X), and wild-type (WT) specimens. Differentially expressed genes (DEGs) were screened in Xbp1 vs. WT, Col vs. WT and CX vs. WT, respectively. Pathway enrichment analysis of these DEGs was performed. Transcription factors (TFs) of the overlapping DEGs were identified. Weighted correlation network analysis (WGCNA) was performed to find modules of DEGs with high correlations, followed by gene function analysis and a protein-protein interaction network construction. In total, 481, 1,530 and 1,214 DEGs were identified in Xbp1 vs. WT, Col vs. WT and CX vs. WT, respectively. These DEGs were enriched in different pathways, such as extracellular matrix (ECM)-receptor interaction and metabolism-related pathways. A total of 7 TFs were found to regulate 19 common upregulated genes, and 4 TFs were identified to regulate 21 common downregulated genes. Two significant gene co-expression modules were enriched and DEGs in the 2 modules were mainly enriched in different biological processes, such as ribosome biogenesis. Moreover, Kras (downregulated), Col5a1 (upregulated) and Furin (upregulated) were both identified in the regulatory networks and protein-protein interaction (PPI) network. On the whole, our findings indicate that the Kras, Col5a1 and Furin genes may play essential roles in the molecular mechanisms of SMCD, which warrants further investigation.

A Japanese familial case of Schmid metaphyseal chondrodysplasia with a novel mutation in <i>COL10A1</i>

Schmid metaphyseal chondrodysplasia (SMCD; OMIM #156500) is an autosomal dominant skeletal dysplasia, characterized by short stature with short legs, bowing of the long bones, and waddling gait. Radiographic features include metaphyseal irregularities with fraying and splaying, and coxa vara, which is defined as a deformity of the hip, wherein the angle between the head and the shaft of the femur is reduced to less than 120 degrees (1). SMCD is caused by heterozygous mutations in COL10A1 (MIM #120110), encoding the α1(X) chains of type X collagen, which is a homotrimeric molecule that consists of three identical α1(X) chains. Each α1(X) chain contains a core triple helical domain, composed of uninterrupted repeats of the Gly-Xaa-Yaa tripeptide, flanked by two globular domains (NC2 and NC1) at both the amino and carboxyl-terminal ends (2). To date, 48 COL10A1 mutations have been reported in families with SMCD of different ethnic origin (Human Gene Mutation Database; http://www.hgmd.cf.ac.uk/ac). Most COL10A1 mutations identified to date were located in the NC1 domain, which contains motifs that promote trimerization of α1(X) chains and subsequent formation of the triple helix to yield stable collagen X molecules. Here, we report a Japanese familial case of SMCD with a novel mutation in COL10A1.

XBP1-Independent UPR Pathways Suppress C/EBP-β Mediated Chondrocyte Differentiation in ER-Stress Related Skeletal Disease

Schmid metaphyseal chondrodysplasia (MCDS) involves dwarfism and growth plate cartilage hypertrophic zone expansion resulting from dominant mutations in the hypertrophic zone collagen, Col10a1. Mouse models phenocopying MCDS through the expression of an exogenous misfolding protein in the endoplasmic reticulum (ER) in hypertrophic chondrocytes have demonstrated the central importance of ER stress in the pathology of MCDS. The resultant unfolded protein response (UPR) in affected chondrocytes involved activation of canonical ER stress sensors, IRE1, ATF6, and PERK with the downstream effect of disrupted chondrocyte differentiation. Here, we investigated the role of the highly conserved IRE1/XBP1 pathway in the pathology of MCDS. Mice with a MCDS collagen X p.N617K knock-in mutation (ColX N617K) were crossed with mice in which Xbp1 was inactivated specifically in cartilage (Xbp1 CartΔEx2), generating the compound mutant, C/X. The severity of dwarfism and hypertrophic zone expansion in C/X did not differ significantly from ColX N617K, revealing surprising redundancy for the IRE1/XBP1 UPR pathway in the pathology of MCDS. Transcriptomic analyses of hypertrophic zone cartilage identified differentially expressed gene cohorts in MCDS that are pathologically relevant (XBP1-independent) or pathologically redundant (XBP1-dependent). XBP1-independent gene expression changes included large-scale transcriptional attenuation of genes encoding secreted proteins and disrupted differentiation from proliferative to hypertrophic chondrocytes. Moreover, these changes were consistent with disruption of C/EBP-β, a master regulator of chondrocyte differentiation, by CHOP, a transcription factor downstream of PERK that inhibits C/EBP proteins, and down-regulation of C/EBP-β transcriptional co-factors, GADD45-β and RUNX2. Thus we propose that the pathology of MCDS is underpinned by XBP1 independent UPR-induced dysregulation of C/EBP-β-mediated chondrocyte differentiation. Our data suggest that modulation of C/EBP-β activity in MCDS chondrocytes may offer therapeutic opportunities.

A Novel COL10A1 Mutation in a Chinese Pedigree with Schmid Type Metaphyseal Chondrodysplasia

Schmid type metaphyseal chondrodysplasia (MCDS) is a kind of autosomal inherited epiphyseal dysplasia caused by a mutation of the COL10A1 gene. Clinical expression of this mutation includes a waddling gait, coxa vara, genu varus or genu valgus and shortened lower limbs among others. To date, over 40 kinds of heterozygous mutations have been identified in the collagen domain of COL10A1 but data on family pedigrees for these is lacking. Nineteen people without a history of interbreeding were selected for the three generations pedigree of MCDS. The proband is a 13 year-old boy with short limbs, hip varus, and tibial varus. In this group, seven people had MCDS (two men, five women). Blood samples for DNA extraction and mutational analysis were collected to sequence the CLO10A1 gene. Chromas atlas analysis and monoclonal sequencing revealed that 7 of the patients in the family are missing a C nucleotide in the third exon of the COL10A1 gene (c.2005delC). The COL10A1 gene mutation results in a frameshift mutation from codon 669, the substitution of 7 amino acids, and premature termination of expression (p.his669thrfsX8). In contrast to the other mutations identified, c.2005delC is close to the C-terminus of the protein sequence and may result in genetic heterogeneity of the Chinese population.

Condrodisplasia metafisaria tipo Schmid: un caso de presentación familiar

Dentro de las displasias óseas hay cuadros clínicos que hacen parte de las denominadas condrodisplasias metafisarias, conocidas también como disostosis metafisarias, las cuales presentan mínimas diferencias entre sí, lo que las hace susceptibles de ser confundidas con otros cuadros clínicos como la acondroplasia y el raquitismo. En este artículo se presenta un caso clínico de condrodisplasia metafisaria tipo Schmid de un paciente de Popayán, Colombia, al igual que algunas consideraciones sobre las principales características clínicas, radiológicas, de diagnóstico y tipo de herencia de esta enfermedad. El caso clínico corresponde a un paciente de género masculino de 23 meses de edad, en quien se inician estudios por la presencia de talla baja desproporcionada. Los resultados mostraron coxa vara, genu varo y extremidades cortas, con un fenotipo similar en la madre y el abuelo materno. Las radiografías evidencian la presencia de irregularidad con “deshilachamiento” de las metáfisis de huesos largos; además, ensanchamiento y esclerosis en las metáfisis proximales de ambos fémur. La meta final es ser confirmado por medio de pruebas genéticas. En conclusión, las condrodisplasias metafisarias, especialmente la tipo Schmid, son enfermedades caracterizadas por talla baja y hallazgos radiológicos especiales, dados principalmente por el compromiso metafisario a nivel de los huesos largos, que en conjunto con las características fenotípicas pueden conducir a la sospecha e identificación de este tipo de patología.

Case of mild Schmid-type metaphyseal chondrodysplasia with novel sequence variation involving an unusual mutational site of the COL10A1 gene

Schmid-type metaphyseal chondrodysplasia (MCDS) is characterized by short stature with short legs, bowing of the long bones, coxa vara, and waddling gait. MCDS is a relatively common form of MCD. Most mutations that cause MCDS occur within the carboxyl-terminal non-collagenous domain (NC1) of the COL10A1 gene. We performed mutational analysis of the COL10A1 genes in 4 unrelated Korean patients with diagnosed MCDS. Mutational analysis of COL10A1 identified c.1904_1915delinsT (p.Gln635LeufsX10) and c.1969dupG (p.Ala657GlyfsX10), 2 novel frameshift mutations, and c.2030T>A (p.Val677Glu) and c.862G>C (p.Gly288Arg) at unusual mutational sites, which could be pathogenic. We present the first report of the molecular characteristics of MCDS in 4 Korean patients. Our findings suggest that a novel sequence variation involving an unusual mutational site of the COL10A1 gene can cause mild MCDS.

Schmid tip metafizyel kondrodisplazi

Schmid type metaphyseal chondrodysplasia Schmid metaphyseal chondrodysplasia is characterized by moderate flaring and irregularity of the metaphyses, but a normal spine and short stature. It is due to mutation of the gene encoding type 10 collogen (COL10AI). Radiologic features include an enlarged proximal femoral epiphysis in early childhood, coxa vara, greather involvement of the distal femoral metaphysis than the proximal, anterior rib changes and normal spine. The radiographic changes are similar to rickets, but calcium and phosphorus metabolism is normal. In this report, we presented a 22 month old male patient who had clinic and radiological findings mimic rickets but with the laboratuary findings

An unfolded protein response is the initial cellular response to the expression of mutant matrilin-3 in a mouse model of multiple epiphyseal dysplasia

Multiple epiphyseal dysplasia (MED) can result from mutations in matrilin-3, a structural protein of the cartilage extracellular matrix. We have previously shown that in a mouse model of MED the tibia growth plates were normal at birth but developed a progressive dysplasia characterised by the intracellular retention of mutant matrilin-3 and abnormal chondrocyte morphology. By 3 weeks of age, mutant mice displayed a significant decrease in chondrocyte proliferation and dysregulated apoptosis. The aim of this current study was to identify the initial post-natal stages of the disease. We confirmed that the disease phenotype is seen in rib and xiphoid cartilage and, like tibia growth plate cartilage is characterised by the intracellular retention of mutant matrilin-3. Gene expression profiling showed a significant activation of classical unfolded protein response (UPR) genes in mutant chondrocytes at 5 days of age, which was still maintained by 21 days of age. Interestingly, we also noted the upregulation of arginine-rich, mutated in early stage of tumours (ARMET) and cysteine-rich with EGF-like domain protein 2 (CRELD2) are two genes that have only recently been implicated in the UPR. This endoplasmic reticulum (ER) stress and UPR did not lead to increased chondrocyte apoptosis in mutant cartilage by 5 days of age. In an attempt to alleviate ER stress, mutant mice were fed with a chemical chaperone, 4-sodium phenylbutyrate (SPB). SPB at the dosage used had no effect on chaperone expression at 5 days of age but modestly decreased levels of chaperone proteins at 3 weeks. However, this did not lead to increased secretion of mutant matrilin-3 and in the long term did not improve the disease phenotype. We performed similar studies with a mouse model of Schmid metaphyseal chondrodysplasia, but again this treatment did not improve the phenotype.Electronic supplementary materialThe online version of this article (doi:10.1007/s12192-010-0193-y) contains supplementary material, which is available to authorized users.