Further evidence for genetic heterogeneity within type II autosomal dominant osteopetrosis.

Type II autosomal dominant osteopetrosis (ADO II) is characterized by an increased bone mass that contrasts with the high frequency of fractures. Linkage analysis performed in an extensive Danish family recently provided evidence for the mapping of an ADO II gene to an 8.5-cM region in chromosome 1p21 between microsatellite markers D1S486 and D1S2792. We recruited, phenotyped, and haplotyped 4F catheter ADO II families including 18 affected subjects and 29 unaffected subjects in order to narrow the candidate region and to search for genetic heterogeneity. ADO II diagnosis was ascertained by the observation of vertebral end plate thickening in at least 2 patients from successive generations. Linkage studies involved five microsatellite markers (D1S486, D1S206, D1S495, D1S248, and D1S2792) spanning 1p21. Haplotype analyses of two of our families clearly excluded the tested locus. The two remaining families gave poorly informative results. These results, combined with those previously reported in two American families, suggest that chromosomal region 1p21 is most likely a minor locus for ADO II.