(provided by candidate): Infantile cortical hyperostosis (Caffey's disease) is a rare genetic disorder with localized thickening of the bone cortex and medullary stenosis, which can appear quite prominently on x-ray. Often, painful swelling occurs over the involved bones. Onset of symptoms is in infancy, and spontaneous resolution occurs before two years of age with no residual effects or recurrences. These clinical findings suggest a transitory, localized defect in the regulation of cortical bone growth, and identification of the responsible genetic defect may serve to enhance the understanding of the growth and maintenance of cortical bone, which remains poorly understood. Pedigrees of families with this disorder show an autosomal dominant pattern of inheritance. No genetic defect associated with this disorder has yet been described, nor has a genetic locus been identified. The candidate has thus far obtained DNA samples from 26 members (19 affected, 1 presumed unaffected, and 6 unrelated spouses) of a large French-Canadian kindred with autosomal dominant inheritance of infantile cortical hyperostosis, and he proposes to use linkage studies to determine the gene locus responsible for this disorder. Once this locus has been identified, the genomic region which is linked to the disease will be delimited by chromosomal crossing-over events in family under study and, potentially, other families with the same disorder. Utilizing sequence information available through the Human Genome Project, genes contained within this linked region will be identified and candidate genes will be selected. Coding regions of candidate genes will be sequenced in genomic DNA from affected individuals (familial and sporadic cases will be studied) to search for mutations which may be responsible for the disorder. Southern blot analyses will also be performed to search for DNA deletions. Once a deletion or mutation (Caffey mutation) is identified in all affected members of the large kindred, the candidate will search for mutations in the same gene in other (smaller) kindreds with Caffey's disease and in sporadic cases, and he will exclude the presence of this mutation in DNA from numerous healthy individuals. Subsequently, the candidate will isolate the murine cDNA homolog and, if this is a novel gene, will study the gene's temporal and spatial patterns of expression by Northern blot analysis. The function of the wild-type protein, along the effects of the Caffey mutation on protein function, will be studied using in-vitro systems. Ultimately, the identification of a protein which may be involved in regulating the thickness and diameter of cortical bone might provide important new insights into the regulation of bone formation and remodeling, and may provide a new target for pharmaceutical agents aimed at reducing the risk of fractures.
| Gensure, Robert C; Makitie, Outi; Barclay, Catherine et al. (2005) A novel COL1A1 mutation in infantile cortical hyperostosis (Caffey disease) expands the spectrum of collagen-related disorders. J Clin Invest 115:1250-7 |
