LOCALIZATION OF A GENE FOR AUTOSOMAL-DOMINANT OSTEOPETROSIS (ALBERS-SCHONBERG-DISEASE) TO CHROMOSOME 1P21

Albers-Schonberg disease, the classical form of osteopetrosis, is an a utosomal dominant condition with generalized increased skeletal densit y due to reduced bone resorption. Characteristic radiological findings are generalized osteosclerosis, with, most typically, endplate sandwi chlike thickening of the vertebrae (Rugger-Jersey spine) and the bone- within-bone (endobones) phenomenon. We studied an extended kindred wit h Albers-Schonberg disease and found linkage with several markers from chromosome 1p21. The Albers-Schonberg gene is located in a candidate region of similar to 8.5 cM flanked by markers D1S486 and D1S2792. A m aximum LOD score (Z(max)) of 4.09 was obtained in multipoint analysis at loci D1S233/D1S248. Possible linkage of osteopetrosis to this chrom osomal region was analyzed because the CSF-1 gene, which is mutated in the op/op mouse model for osteopetrosis, is located in 1p21. However, SSCP and mutation analysis in patients did not reveal any abnormality , which excludes the CSF-1 gene as the disease-causing gene. This was confirmed by refined physical mapping of the CSF-1 gene outside the ca ndidate region for the Albers-Schonberg gene. The identification of th e molecular defect underlying Albers-Schonberg disease will therefore be dependent on the isolation of other genes from an 8.5-cM candidate region on chromosome 1p21.