Double-layered patella in multiple epiphyseal dysplasia is not exclusive toDTDST mutation

Nakashima, Eiji; Ikegawa, Shiro; Ohashi, Hirofumi; Kimizuka, Mamori; Nishimura, Gen

doi:10.1002/ajmg.a.30481

Cited by 21 publications

(15 citation statements)

References 6 publications

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“…One patient had a double-layered patella. Previous studies have reported that the double-layered patella is specific to DTDST mutations [Superti-Furga et al, 1999;Unger and Hecht, 2001]; however, this patient's family history was consistent with autosomal dominant inheritance, and he was found to have a COL9A2 mutation [Nakashima et al, 2005a]. Sixteen patients showed a positive family history.…”

Section: Resultsmentioning

confidence: 80%

Comprehensive screening of multiple epiphyseal dysplasia mutations in Japanese population

Itoh¹,

Shirahama²,

Nakashima

et al. 2006

American J of Med Genetics Pt A

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Multiple epiphyseal dysplasia (MED) is among the most genetically heterogeneous skeletal dysplasias. Six genes involved in MED, COMP, MATN3, COL9A1, COL9A2, COL9A3, and DTDST have been identified; however, the presence of additional disease genes has been reported, and the detection rate for mutations in known genes accounts for no more than 50% of patients with MED in Western populations. Here, we screened the six known disease genes in 35 consecutive Japanese MED patients. We analyzed the entire coding region of each gene, along with flanking intron-exon junctions, by direct sequencing. A total of 19 mutations were identified in COMP, MATN3, COL9A2, COL9A3, and DTDST. The detection rate for known mutations was higher in this study than in previous reports, and we identified a substantially different spectrum of mutations. Mutations in MATN3 were more prevalent among these Japanese patients, whereas no DTDST mutations were detected. Most of the mutations were localized within specific regions of each gene: COMP mutations were found in the calmodulin-like repeat domains; MATN3 mutations in the von Willebrand factor type A domain; and type IX collagen gene mutations occurred in the third collagenous domains. Based on the integration of clinical and genetic information, we propose an algorithm for detecting mutations in Japanese MED patients. Our study further supports the existence of additional MED gene(s).

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Section: Resultsmentioning

confidence: 80%

Comprehensive screening of multiple epiphyseal dysplasia mutations in Japanese population

Itoh¹,

Shirahama²,

Nakashima

et al. 2006

American J of Med Genetics Pt A

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“…In humans, mutations in COL9A2 and COL9A3 have been associated with multiple epiphyseal dysplasia (MED, EDM2 and EDM3 for COL9A2 and COL9A3 mutations, respectively), (Bonnemann et al , 1999; Paasilta et al , 1999; Holden et al , 1999; Lohiniva et al , 2000; Fiedler et al , 2002; Nakashima et al , 2005a; Nakashima et al , 2005b; Takahashi et al , 2006). MED is one of the common forms of skeletal dysplasia, characterized by a delay in the appearance of the epiphyses, irregular epiphyseal formation, mild short stature, and early-onset osteoarthiritis (Spranger et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

COL9A2 and COL9A3 mutations in canine autosomal recessive oculoskeletal dysplasia

et al. 2010

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Oculo-skeletal dysplasia segregates in two canine breeds, the Labrador retriever and samoyed, in which the causative loci have been termed drd1 and drd2, respectively. Affected dogs exhibit short-limbed dwarfism together with severe ocular defects, and this phenotype is inherited as an autosomal recessive trait in both breeds. The clinical and pathological appearance resembles human hereditary arthro-ophthalmopathies such as Stickler syndrome, or Marshall Syndrome, although these human disorders are usually dominant. Linkage studies in drd1-informative pedigrees mapped the locus to canine chromosome 24, and led to the identification of an insertional mutation in exon 1 of the gene COL9A3 that cosegregates with the disease. The drd2 locus was similarly mapped to canine chromosome 15 and shown to cosegregate with a 1,267 bp deletion mutation in the 5′ end of COL9A2. Both mutations affect the COL3 domain of the respective gene. Northern analysis showed reduced RNA expression in affected retina compared to normal. These models offer potential for studies such as protein-protein interactions between different members of the collagen gene family; regulation and expression of these genes in retina and cartilage, and even opportunities for gene therapy.

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“…Less than 5% of the mutations that are known to cause dominant MED are located in the COL9A2 gene; this type of MED is defined as EDM2 (Briggs and Chapman 2002, Jakkula et al 2005). The EDM2 mutations are all located at different positions within the donor splice site of intron 3 and result in an in-frame deletion of 12 amino acids from the COL3 domain of the collagen chain (Holden et al 1999, Spayde et al 2000, Fiedler et al 2002, Nakashima et al 2005, Takahashi et al 2006). The COL3 domain has proven to be essential for the binding between collagen IX and MATN3, an extracellular matrix protein in cartilage (Fresquet et al 2007).…”

Section: Discussionmentioning

confidence: 99%

Multiple epiphyseal dysplasia

et al. 2009

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Background Multiple epiphyseal dysplasia (MED) is a common genetically and clinically heterogeneous skeletal dysplasia characterized by early-onset osteoarthritis, mainly in the hip and knee, and mild-to-moderate short stature. Here we report on a 6-generation MED family with 17 affected members.Method The clinical and radiographic data on the 12 affected members still living were scrutinized. A structured inquiry comprising state of health and MED-related symptoms since birth up to the present time and the osteoarthritis outcome (KOOS) questionnaire were sent to all living family members with MED. The 5 known gene loci for autosomal dominant MED were analyzed for linkage, using fluorescence-labeled microsatellite markers. Linkage was ascertained with markers close to the COL9A2 gene, which was analyzed for mutations by sequencing.Results We identified an exon 3 donor splice mutation in the COL9A2 gene in all affected family members. Clinical, radiographic, and questionnaire data from affected family members suggested that MED caused by COL9A2 mutations starts in early childhood with knee pain accompanied by delayed ossification of femoral epiphyses. The disease then either stabilizes during puberty or progresses with additional joints becoming affected; joint surgery might be necessary. The progression of the disease also affects muscles, with increasing atrophy, resulting in muscle fatigue and pain. Muscular atrophy has not been reported earlier in cases with COL9A2 mutations.Interpretation In a patient with clinically suspected or verified MED, it is important to perform DNA-based analysis to identify a possible disease-causing mutation. This information can be used to carry out genetic risk assessment of other family members and to achieve an early and correct diagnosis in the children.

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Double-layered patella in multiple epiphyseal dysplasia is not exclusive toDTDST mutation

Cited by 21 publications

References 6 publications

Comprehensive screening of multiple epiphyseal dysplasia mutations in Japanese population

Comprehensive screening of multiple epiphyseal dysplasia mutations in Japanese population

COL9A2 and COL9A3 mutations in canine autosomal recessive oculoskeletal dysplasia

Multiple epiphyseal dysplasia

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