Familial multiple epiphyseal dysplasia due to a matrilin‐3 mutation: Further delineation of the phenotype including 40 years follow‐up

Mostert, Adriaan K.; Dijkstra, P. F.; Jansen, B.; Horn, J.R. van; Graaf, Bianca de; Heutink, Peter; Lindhout, Dick

doi:10.1002/ajmg.a.20034

Cited by 40 publications

(34 citation statements)

References 15 publications

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“…As in the other forms of MED, 6,15 however, there may exist a 'window of opportunity' in mid-childhood for differentiating these forms from each other, since the radiographic findings become less characteristic towards closure of the growth plates. Arg 718 Trp 9 and Ala 735 Val (this study) mutations in C-terminus of COMP seem to associate with myopathic symptoms which are similar to those seen in patients with a COL9A3 mutation. 23,24 Some heterozygous changes in DTDST were identified in MED patients, but, since all disorders caused by DTDST mutations are recessive, 16 these changes are unlikely to affect MED phenotype; the existence of a second, unidentified mutation in a region not analysed cannot be ruled out.…”

Section: New Phenotypic Entities Two Distinctive New Phenotypic Entitsupporting

confidence: 73%

Mutations in the known genes are not the major cause of MED; distinctive phenotypic entities among patients with no identified mutations

et al. 2004

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Multiple epiphyseal dysplasia (MED) is a clinically and genetically heterogeneous chondrodysplasia. Mutations in six genes (COMP, COL9A1, COL9A2, COL9A3, MATN3 and DTDST) have been reported, but the genotype -phenotype correlations and the proportions of cases due to mutations in these genes are still not well characterized. We performed a clinical, radiological and molecular analysis of known MED genes on 29 consecutive MED patients. The mutation analysis resulted in identification of the DTDST mutation in four patients (14%), the COMP mutation in three (10%) and the MATN3 mutation in three (10%). Thus, a disease-causing mutation was identified in 10 patients altogether (34%). The phenotypic features observed in the patients with mutations were in accordance with previously described phenotypes, but two new distinct phenotypic entities were identified in patients in whom no mutation was found. One of them was characterized by severe, early-onset dysplasia of the proximal femurs with almost complete absence of the secondary ossification centres and abnormal development of the femoral necks. The other phenotype was characterized by 'mini-epiphyses', resulting in severe dysplasia of the proximal femoral heads. The findings suggest that mutations in the known genes are not the major cause of MED and are responsible for less than half of the cases. The existence of additional MED loci is supported by the exclusion of known loci by mutation analysis and finding of specific subgroups among these patients.

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Section: New Phenotypic Entities Two Distinctive New Phenotypic Entitsupporting

confidence: 73%

Mutations in the known genes are not the major cause of MED; distinctive phenotypic entities among patients with no identified mutations

et al. 2004

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“…A mild form of the autosomal dominant MED is caused by missense mutations (V194D and R121D) in the second exon of the MATN3 gene encoding the vWFA domain (7). Another missense mutation in the same region of MATN3 (A128P) was discovered recently in a family with bilateral hereditary microepiphyseal dysplasia, which is known to be a distinct variant form of MED (22). These mutations were suggested to alter the folding and/or function of the vWFA domain, indicating that the disorder is most probably due to a dominant-negative effect rather than being caused by haploinsuffiency (6,7).…”

Section: Discussionmentioning

confidence: 99%

“…Other mutations in matrilin-3 have been shown to cause multiple epiphyseal dysplasia (MED), a form of osteochondrodysplasia characterized by delayed and irregular ossification of the epiphyses and early-onset osteoarthritis (6,7), and bilateral hereditary microepiphyseal dysplasia, a MED-like disorder characterized by small epiphyses in the hip and the knee joint (22). It is still not clear if these diseases are caused by a loss of matrilin-3 function or by a dominant-negative effect of the mutant protein on chondrocyte viability or extracellular matrix assembly.…”

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confidence: 99%

Matrilin-3 Is Dispensable for Mouse Skeletal Growth and Development

Kobbe

Nicolae

et al. 2004

Molecular and Cellular Biology

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Matrilin-3 belongs to the matrilin family of extracellular matrix (ECM) proteins and is primarily expressed in cartilage. Mutations in the gene encoding human matrilin-3 (MATN-3) lead to autosomal dominant skeletal disorders, such as multiple epiphyseal dysplasia (MED), which is characterized by short stature and earlyonset osteoarthritis, and bilateral hereditary microepiphyseal dysplasia, a variant form of MED characterized by pain in the hip and knee joints. To assess the function of matrilin-3 during skeletal development, we have generated Matn-3 null mice. Homozygous mutant mice appear normal, are fertile, and show no obvious skeletal malformations. Histological and ultrastructural analyses reveal endochondral bone formation indistinguishable from that of wild-type animals. Northern blot, immunohistochemical, and biochemical analyses indicated no compensatory upregulation of any other member of the matrilin family. Altogether, our findings suggest functional redundancy among matrilins and demonstrate that the phenotypes of MED disorders are not caused by the absence of matrilin-3 in cartilage ECM.

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“…Of the 12 MATN3 mutations reported to date, 10 of these affect residues in the 6 β-strands, indeed mutations have now been reported in 5 of the 6 β-strands that comprise the β-sheet (Cotterill, et al, 2005;Jackson, et al, 2004;Mabuchi, et al, 2004;Maeda, et al, 2005;Mostert, et al, 2003). The two exceptions to this rule are p.Arg70His, located in a linker region and only 7 residues downstream from the amino-terminal cysteine residue of the A-domain (Maeda, et al, 2005), and p.Phe105Ser in the α1 helix of the A-domain (Mabuchi, et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

“…Many of the mutations in these genes cluster in distinct DOI: 10.1002/humu.9518 regions of the protein and usually affect conserved residues that are important for the structure and/or function of the relevant gene products (Briggs and Chapman, 2002). This is particularly the case with MATN3 and to date all MED-causing mutations affect residues within, or closely associated with, the single A-domain of matrilin-3 (Cotterill, et al, 2005;Jackson, et al, 2004;Mabuchi, et al, 2004;Maeda, et al, 2005;Mostert, et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Novel mutations in exon 2 ofMATN3affect residues within the α-helices of the A-domain and can result in the intracellular retention of mutant matrilin-3

et al. 2008

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Multiple epiphyseal dysplasia (MED) is a clinically variable and genetically heterogeneous chondrodysplasia characterized by mild to moderate short stature and early onset osteoarthritis. Some forms of MED result from mutations in the gene encoding the cartilage structural protein matrilin-3 (MATN3). The majority of MATN3 mutations affect conserved residues within the β-sheet of the single A-domain of matrilin-3. These mutations cause the protein to misfold and prevent its secretion from the rER, both in vitro and in vivo. More recently a single mutation (p.Phe105Ser) has been identified within the α1 -helix of the Adomain, but its affect on the structure and/or function of matrilin-3 is unknown. In this paper we describe the characterization of two additional α-helical mutations (p.Ala173Asp and p.Lys231Asn) and show that both p.Phe105Ser and pAla173Asp prevent the secretion of A-domain in vitro. In contrast, p.Lys231Asn does not prevent the secretion of matrilin-3 Adomain, nor does it disrupt the structure of this domain or inhibit its binding to type II or type IX collagen. Therefore, despite extensive biochemical analysis the disease mechanism of p.Lys231Asn remains unresolved and care should be taken in counseling for these types of mutation in MATN3.

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Familial multiple epiphyseal dysplasia due to a matrilin‐3 mutation: Further delineation of the phenotype including 40 years follow‐up

Cited by 40 publications

References 15 publications

Mutations in the known genes are not the major cause of MED; distinctive phenotypic entities among patients with no identified mutations

Mutations in the known genes are not the major cause of MED; distinctive phenotypic entities among patients with no identified mutations

Matrilin-3 Is Dispensable for Mouse Skeletal Growth and Development

Novel mutations in exon 2 ofMATN3affect residues within the α-helices of the A-domain and can result in the intracellular retention of mutant matrilin-3

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