A novel COL1A1 mutation in infantile cortical hyperostosis (Caffey disease) expands the spectrum of collagen-related disorders
Year: 2005
Type: article
Study design: Observational Study
Abstract: Infantile cortical hyperostosis (Caffey disease) is characterized by spontaneous episodes of subperiosteal new bone formation along 1 or more bones commencing within the first 5 months of life. A genome-wide screen for genetic linkage in a large family with an autosomal dominant form of Caffey disease (ADC) revealed a locus on chromosome 17q21 (LOD score, 6.78). Affected individuals and obligate carriers were heterozygous for a missense mutation (3040Ctwo head right arrowT) in exon 41 of the gene encoding the alpha1(I) chain of type I collagen (COL1A1), altering residue 836 (R836C) in the triple-helical domain of this chain. The same mutation was identified in affected members of 2 unrelated, smaller families with ADC, but not in 2 prenatal cases and not in more than 300 chromosomes from healthy individuals. Fibroblast cultures from an affected individual produced abnormal disulfide-bonded dimeric alpha1(I) chains. Dermal collagen fibrils of the same individual were larger, more variable in shape and size, and less densely packed than those in control samples. Individuals bearing the mutation, whether they had experienced an episode of cortical hyperostosis or not, had joint hyperlaxity, hyperextensible skin, and inguinal hernias resembling symptoms of a mild form of Ehlers-Danlos syndrome type III. These findings extend the spectrum of COL1A1-related diseases to include a hyperostotic disorder.
DOI: 10.1172/jci200522760
Institutions: Harvard University, Massachusetts General Hospital, Helsinki University Hospital, Hospital for Sick Children, Howard Hughes Medical Institute, Women's and Children's Hospital, Women's and Children's Health Network, The University of Adelaide, Max Planck Institute for Molecular Genetics, Children's Hospital at Westmead, Westmead Hospital, University of Oulu
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: bronze
Funders: Massachusetts General Hospital, European Society for Paediatric Endocrinology, Novo Nordisk, Lastentautien Tutkimussäätiö, National Institutes of Health, U.S. Public Health Service, Canadian Institutes of Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Canadian Arthritis Network
OpenAlex ID: W2162444478