The molecular genetics of Scheuermann disease

Dr Jane Bleasel (MBBS, PhD)1, Dr Shireen Lamandé (PhD)2, Prof. John Bateman (PhD) 2, A/Prof Ravi Savarirayan (MBBS, PhD)2, Dr Melita Irving (MBBS)2, Ms Helen Lescesen2

1 Department of Rheumatology, RPA Institute of Rheumatology & Orthopaedics, Missenden Rd., Camperdown, NSW, 2050
2 Musculoskeletal Disorders, Murdoch Childrens Research Institute, The Royal Children’s Hospital, Flemington Road, Parkville, Victoria 3052

Background

Scheuermann disease (SD) is a common condition causing progressive curvature of the spine (kyphosis) with adolescent onset. In a number of cases it is inherited and follows an autosomal dominant pattern with reduced penetrance, such that some individuals in a family who are carriers of a genetic susceptibility to SD do not have the condition. It is likely SD is due to multiple factors, with a number of separate genes likely to be implicated in the disorder. The spinal deformity in SD is secondary to the progressive development of wedge-shaped vertebral bodies, the consequence of a fundamental defect in the cartilaginous end plates. This project funded by SpinCare Australia, aimed to determine the molecular pathology underlying SD, providing insights not only into SD itself but also the mechanisms involved in spinal development and other conditions with developmental spinal abnormalities. 

Work to Date

The project centred upon a large, three-generation family in New South Wales. DNA samples from a number of affected and unaffected individuals have been collected, and the Australian Genome Research Facility (AGRF) has undertaken 10K SNP chip linkage analysis. This identified two genomic regions where the gene of interest in this family is expected to lie. One genomic region appeared more promising than the other, since the linkage data was stronger. Within this locus, 11 genes of known function and seven hypothetical genes were identified. Although the function of some of these genes and the known expression patterns determined from pre-existing data suggested a possible role in causing SD, no mutations have been identified following complete direct sequencing of all 18 genes.

Future Work

Further work is now planned to determine whether the first region can be excluded and for attention to be turned to the second, larger region. It is hoped that this will be achieved through the following:

  • Further clinical evaluation of certain family members – the determination of the affected status of four members will allow better interpretation of the linkage data and, in particular, the detection of the presence of a condition mimicking SD will clarify discrepancies in the linkage data.
  • Further molecular analysis through SNP linkage – the inclusion of five further individuals may strengthen the linkage data and provide further confirmation that the gene of interest lies within the region of focus.
  • Further molecular analysis through gene dosage studies – this will allow larger exonic or whole gene deletions to be detected.
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