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Clinical and genetic studies of three inherited skeletal disorders
Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Mutations in genes of importance for cartilage development may lead to skeletal malformations, chondroskeletal dysfunction and increased susceptibility to degenerative joint disease. Characterization of these mutations and identification of molecular pathways for the corresponding gene products have contributed to our understanding of mechanisms regulating skeletal patterning, endochondral ossification and joint formation.

A five generation family segregating autosomal dominant osteochondritis dissecans (OCD) was identified. Affected family members presented with OCD in knees, hips and elbows, short stature, and early osteoarthritis. A genome wide scan and a multipoint linkage analysis identified aggrecan (ACAN) as a prime candidate gene. DNA sequence analysis of the ACAN-gene revealed heterozygosity for a missense mutation (c.6907G>A) in affected subjects, resulting in a p.V2303M substitution in the aggrecan G3 domain C-type lectin. This domain is important for the interaction with other proteins in the cartilage extracellular matrix. To determine the effect of the V2303M substitution on secretion and interaction, we performed binding studies with recombinant mutated and wild type G3 proteins. We found decreased affinity or complete loss of interaction between V2303M aggrecan and fibulin1, fibulin2 and tenascin-R. Analysis of articular cartilage from an affected family member confirmed that V2303M aggrecan is produced and present.

In search for gene mutations associated with multiple epiphyseal dysplasia (MED) we considered the ACAN-gene a likely candidate. The ACAN-gene was analysed in 39 individuals with MED and screened negative for mutations in six previously known MED genes. Sequence analysis revealed a heterozygous missense mutation (c.1448G>T) in one adult male and compound heterozygous missense mutations (c.1366T>C and c.836G>A) in a five year old boy with healthy parents, each of them carrier for one of the mutations.

A large family segregating autosomal dominant brachymesophalangia and OCD in finger joints was characterised. The clinical presentation in six affected family members was consistent with the diagnosis Brachydactyly type A1, in this family characterized by shortening of the middle phalanges, short ulnar styloid process, flattening of the metacarpal heads and mild osteoarthritis. The condition may be caused by mutations in the Indian hedgehog gene (IHH) or a yet unidentified gene on chromosome 5p13. Sequence analysis of the IHH-gene in affected individuals revealed a novel C to T transition (c.472C>T) leading to a p.158Arg>Cys substitution. Residue 158 in IHH is highly conserved throughout evolution and molecular structure modelling of IHH suggests that the R158C substitution leads to a conformational change at the site of interaction with the IHH-receptor. This supports that the substitution causes Brachydactyly type A1 in this family.

In summary, we report on the clinical, radiological and molecular genetic characteristics of the three skeletal disorders OCD, MED and BDA1. Our results provide a novel molecular mechanism in the pathophysiology of familial osteochondritis dissecans confirming the importance of aggrecan C-type lectin for cartilage function. We also show that ACAN-gene mutations may be associated with MED extending the spectrum of skeletal dysplasias associated with the aggrecan gene. Finally, we report on a novel missense mutation in a conserved region of the IHH-gene associated with BDA1.

Place, publisher, year, edition, pages
2009. , 55 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1259
Keyword [en]
skeletal disorders, osteochondritis dissecans, ACAN-gene, multiple epiphyseal dysplasia, brachydactyly type A1, IHH-gene
National Category
Medical Genetics
Research subject
Clinical Genetics
Identifiers
URN: urn:nbn:se:umu:diva-22402ISBN: 978-91-7264-753-4 (print)OAI: oai:DiVA.org:umu-22402DiVA: diva2:216272
Public defence
2009-05-29, 09:00 (English)
Opponent
Supervisors
Available from: 2009-05-11 Created: 2009-05-07 Last updated: 2010-01-18Bibliographically approved
List of papers
1. Familial osteochondritis dissecans associated with early osteoarthritis and disproportionate short stature
Open this publication in new window or tab >>Familial osteochondritis dissecans associated with early osteoarthritis and disproportionate short stature
2008 (English)In: Osteoarthritis and Cartilage, ISSN 1063-4584, E-ISSN 1522-9653, Vol. 16, no 8, 890-896 p.Article in journal (Refereed) Published
Abstract [en]

Objective: Familial osteochondritis dissecans (OCD) is a rare disorder characterised by disturbed chondro-skeletal development, disproportionate growth and deformation of the skeleton.

Design: We identified a five-generation family with 15 living affected members from Northern Sweden. The disorder was diagnosed with a case definition of OCD in at least one joint.

Results: Main clinical findings consisted of OCD in knees and/or hips and/or elbows, disproportionate short stature and early osteoarthritis (OA). There were no radiological indications of epiphyseal dysplasia. Anthropometric measurements of affected individuals showed short stature, a high ratio between sitting height and total height, a relatively normal arm span and head circumference. In 12 of 15 cases, onset was during late childhood or adolescence and OA had developed in seven of those patients.

Conclusions: Our observation suggests that OA is a frequent complication in familial OCD even though the lesions appear before closure of physis.

Place, publisher, year, edition, pages
London: Published for the Society by Baillière Tindall, 2008
Keyword
Familial osteochondritis dissecans; Osteoarthritis; Skeletal dysplasia; Autosomal dominant; Cartilage
Identifiers
urn:nbn:se:umu:diva-22382 (URN)10.1016/j.joca.2007.11.009 (DOI)
Available from: 2009-05-07 Created: 2009-05-07 Last updated: 2011-03-24Bibliographically approved
2. A missense mutation in the aggrecan C-type lectin domain disrupts extracellular matrix interactions and causes dominant familial osteochondritis dissecans with short stature and early osteoarthritis
Open this publication in new window or tab >>A missense mutation in the aggrecan C-type lectin domain disrupts extracellular matrix interactions and causes dominant familial osteochondritis dissecans with short stature and early osteoarthritis
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(English)Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-22383 (URN)
Available from: 2009-05-07 Created: 2009-05-07 Last updated: 2010-01-14Bibliographically approved
3. Mutations in the aggrecan gene (ACAN) are associated with multiple epiphyseal dysplasia
Open this publication in new window or tab >>Mutations in the aggrecan gene (ACAN) are associated with multiple epiphyseal dysplasia
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(English)Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-22386 (URN)
Available from: 2009-05-07 Created: 2009-05-07 Last updated: 2010-01-14Bibliographically approved
4. Brachydactyly type A1 associated with unusual radiological findings and a novel mutation in the Indian Hedgehog (IHH) gene
Open this publication in new window or tab >>Brachydactyly type A1 associated with unusual radiological findings and a novel mutation in the Indian Hedgehog (IHH) gene
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(English)Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-22387 (URN)
Available from: 2009-05-07 Created: 2009-05-07 Last updated: 2010-10-14Bibliographically approved

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