Localization of a Gene for Autosomal Dominant Osteopetrosis (Albers-Schönberg Disease) to Chromosome 1p21

Abstract

Albers-Schönberg disease, the classical form of osteopetrosis, is an autosomal dominant condition with generalized increased skeletal density due to reduced bone resorption. Characteristic radiological findings are generalized osteosclerosis, with, most typically, end-plate sandwichlike thickening of the vertebrae (Rugger-Jersey spine) and the bone-within-bone (endobones) phenomenon. We studied an extended kindred with Albers-Schönberg disease and found linkage with several markers from chromosome 1p21. The Albers-Schönberg gene is located in a candidate region of approximately 8.5 cM flanked by markers D1S486 and D1S2792. A maximum LOD score (Z(max)) of 4.09 was obtained in multipoint analysis at loci D1S239/D1S248. Possible linkage of osteopetrosis to this chromosomal 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 candidate region for the Albers-Schönberg gene. The identification of the molecular defect underlying Albers-Schönberg disease will therefore be dependent on the isolation of other genes from an 8.5-cM candidate region on chromosome 1p21.

EXTL2, a Member of the EXT Family of Tumor Suppressors, Controls Glycosaminoglycan Biosynthesis in a Xylose Kinase-dependent Manner

“…Based on these findings, we propose that EXTL2 plays an important role in the regulation of GAG synthesis in concert with FAM20B and that an imbalance between EXTL2 and FAM20B functions may lead to abnormal endochondral ossification. Moreover, the EXTL2 gene was localized to chromosome 1q11-12, a position adjacent to the chromosomal location of the CSF-1 gene, which is mutated in the op/op mouse model for osteopetrosis (35). EXTL2 might be also associated with pathological conditions such as osteopetrosis.…”

Case Reports: Treatment of Subtrochanteric and Ipsilateral Femoral Neck Fractures in an Adult with Osteopetrosis

“…The chloride channel mutation appears associated with the autosomal-dominant form [14,19,34]. The mutation responsible for autosomal-dominant form Type II has been localized to two possible chromosomal locations, 1p21 and 16p13.3 [8,41]. Others have suggested the genetic defect in osteopetrosis leads to failure to produce colony-stimulating factor 1, which regulates osteoclast development and differentiation [1].…”

Recent progress in understanding the genetic susceptibility to osteoporosis

“…Linkage analyses in families at high-risk for rare metabolic bone diseases should also yield important clues to the pathogenesis of osteoporosis. Recent examples are the mapping of loci for both high [Johnson et al, 1997] and low [Gong et al, 1996] bone mass to chromosome 11q and osteopetrosis to chromosome 1p [Van Hul et al, 1997]. Similar ongoing studies in baboons [Rogers and Hixson, 1997] and mice [Beamer et al, 1997] may reveal additional loci whose human homologs contribute to osteoporotic risk.…”