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Precocious Osteoarthritis in a Family with Recurrent COL2A1 Mutation
KERRI M. CARLSON, KAREN M. YAMAGA, KENT A. REINKER, YUJEN E. HSIA, CLYDE CARPENTER, LUCIENNE M. ABE, ANDREA K. PERRY, DONALD A. PERSON, DOUGLAS A. MARCHUK, and ELLEN M. RANEY ABSTRACT. Objective. To examine the genotypic and phenotypic characteristics of a Micronesian kindred with autosomal dominant precocious osteoarthritis (OA). Methods. We reviewed records and radiographs of 3 index patients and their parents, administered questionnaires to 16 additional kindred members, performed whole-genome scans of 24 family members, and sequenced relevant genes from 16 family members. Results. The kindred displayed early onset OA, enlarged epiphyses, platyspondyly, and brachydactyly with dysplastic findings consistent with mild spondyloepiphyseal dysplasia. Genetic analysis revealed an arginine to cysteine substitution at position 75 of the collagen 2A1 gene, a mutation that has been described in 4 other geographically distinct families. The major phenotypic differences among the families were in height (ranging from short to tall) and hearing loss noted in 3 of the 5 families. Conclusion. The presence of the COL2A1 Arg75Cys mutation in 5 geographically distinct areas helps to confirm a potential mutational hotspot. The diverse phenotypic spectrum suggests that modifier genes and environmental factors play a role in the expression of this mutation. (J Rheumatol 2006;33:1133–6) Key Indexing Terms:
COLLAGEN
From the Shriners Hospital for Children and John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, USA. Supported by the Victoria and Bradley Geist Foundation, Honolulu, Hawaii, USA. K.M. Carlson, PhD, Graduate Research Assistant, Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina; D.A. Marchuk, PhD, Professor, Department of Molecular Genetics and Microbiology, Director, Center for Experimental Genetics, Duke University Medical Center; K.A. Reinker, MD, Associate Professor, Department of Orthopaedic Surgery, University of Texas Health Science Center at San Antonio, San Antonio, Texas; C.T. Carpenter, MD, Pediatric Orthopedic Fellow, Shriners Hospital for Children; K.M. Yamaga, PhD, Professor, Department of Tropical Medicine, Medical Microbiology and Pharmacology, John A. Burns School of Medicine, University of Hawaii; Y.E. Hsia, MD, Emeritus Professor, Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii; L.M. Abe, PhD, Research Affiliate; A.K. Perry, BS, Research Assistant, Department of Tropical Medicine, Medical Microbiology and Pharmacology, John A. Burns School of Medicine, University of Hawaii; D.A. Person, MD, Departments of Clinical Investigation and Pediatrics, Tripler Army Medical Center, Clinical Professor, Department of Pediatrics, John A. Burns School of Medicine, University of Hawaii; E.M. Raney, MD, Chief of Staff, Shriners Hospital for Children, Clinical Professor, John A. Burns School of Medicine, University of Hawaii. Address reprint requests to Dr. E.M. Raney, Shriners Hospital for Children, 1310 Punahou Street, Honolulu, HI 96826-1099. E-mail: eraney@shrinenet.org Accepted for publication January 30, 2006.
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