An Unbalanced Rearrangement of Chromosomes 4:20 is Associated with Childhood Osteoporosis and Reduced Caspase-3 Levels.
The purpose of this study was to investigate the association of a chromosome 4:20 imbalance with osteoporosis in three related children. Bone biochemistry, bone turnover markers, and dual-energy X-ray absorptiometry (DXA) scanning were performed in all three cases and bone biopsy and histomorphometry in one. The chromosome imbalance was delineated by array comparative genomic hybridization (aCGH) and analyzed for candidate genes. A potential candidate gene within the deleted region is caspase-3, previously linked to low bone mineral density (BMD) in heterozygous mice thus caspase-3 activity was measured in cases and controls. Routine bone biochemistry and markers of bone turnover did not reveal any abnormality. DXA showed reduced total and lumbar spine bone mineral content. aCGH showed an 8 megabase (Mb) deletion of terminal chromosome 4q incorporating a region previously linked to low BMD and a 15 Mb duplication of terminal chromosome 20p. Bone biopsy showed a high bone turnover state, trabecularisation of cortical bone and numerous small osteoclasts coupled with normal bone formation. Basal serum caspase-3 activity was lower in cases compared with controls. We conclude that the early-onset osteoporosis with low basal levels of caspase-3 and abnormal osteoclasts is a feature of this chromosomal translocation. Further investigation of the role of the deleted and duplicated genes and especially caspase-3 is required.
Department of Clinical Genetics, Laboratory Medicine Building, Southern General Hospital, Glasgow, Scotland.
Esther
E
Kinning
Child Health, School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Scotland.
Martin
M
McMillan
Child Health, School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Scotland.
Sheila
S
Shepherd
Musculoskeletal Programme, Division of Applied Medicine, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, Scotland.
Miep
M
Helfrich
Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, United Kingdom.
Rob Vant
RV
Hof
National Paediatric Spinal Deformity Service, Royal Hospital for Sick Children, Edinburgh, Scotland.
Christopher
C
Adams
Child Health, School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Scotland.
Heather
H
Read
Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Scotland.
Daniel M
DM
Wall
Child Health, School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Scotland.
S Faisal
SF
Ahmed
bone histomorphometry; caspase; chromosome translocation; osteoclast; osteoporosis