Mapping of autosomal dominant osteopetrosis type II (Albers-Schönberg disease) to chromosome 16p13.3

Abstract

The osteopetroses are a heterogeneous group of conditions characterized by a bone-density increase due to impaired bone resorption. As well as the two or more autosomal recessive types, two autosomal dominant forms of osteopetrosis, differentiated by clinical and radiological signs, are described. Autosomal dominant osteopetrosis (ADO) type II, also known as "Albers-Schönberg disease," is characterized by sclerosis, predominantly involving the spine (vertebral end-plate thickening, or Rugger-Jersey spine), the pelvis ("bone-within-bone" structures), and the skull base. An increased fracture rate can be observed in these patients. By linkage analysis, the presence, on chromosome 1p21, of a gene causing ADO type II was previously suggested. However, analysis of further families with ADO type II indicated genetic heterogeneity within ADO type II, with the chromosome 1p21 locus being only a minor locus. We now perform a genomewide linkage scan of a French extended family with ADO type II, which allows us to localize an ADO type II gene on chromosome 16p13.3. Analysis of microsatellite markers in five further families with ADO type II could not exclude this chromosomal region. A summed maximum LOD score of 12.70 was generated with marker D16S3027, at a recombination fraction (straight theta) of 0. On the basis of the key recombinants in the families, a candidate region of 8.4 cM could be delineated, flanked by marker D16S521, on distal side, and marker D16S423, on the proximal side. Surprisingly, one of the families analyzed is the Danish family previously suggested to have linkage to chromosome 1p21. Linkage to chromosome 16p13.3 clearly cannot be excluded in this family, since a maximum LOD score of 4.21 at theta=0 is generated with marker D16S3027. Because at present no other family with ADO type II has proved to have linkage to chromosome 1p21, we consider the most likely localization of the disease-causing gene in this family to be to chromosome 16p13.3. This thus reopens the possibility that ADO type II is genetically homogeneous because of a single gene on chromosome 16p13.3.

Figure 1

Radiological features of female patient CII-2 at age 45 years. A, Lumbar-spine standard radiograph showing thickened and sclerotic vertebral end plates. This feature, usually named “Rugger-Jersey spine,” is characteristic of ADO type II. B, Pelvic-front standard radiograph with bone-within-bone sign—usually consisting of concentric bands of sclerosis in round and flat bones, especially in the iliac wings.

Figure 2

A–F, Pedigrees of families A–F, respectively. Squares represent males, and circles represent females. Blackened symbols indicate affected individuals, and unblackened symbols indicate individuals without clinical or radiological signs. The haplotypes from the chromosome 16p13.3 markers are shown below the symbols. The order of the seven markers analyzed is, from telomere (top) to centromere (bottom), D16S521, D16S3024, D16S3082, D16S3027, D16S423, D16S3030, and D16S3128. Blackened bars indicate the haplotype that cosegregates with the disease.

Figure 2

A–F, Pedigrees of families A–F, respectively. Squares represent males, and circles represent females. Blackened symbols indicate affected individuals, and unblackened symbols indicate individuals without clinical or radiological signs. The haplotypes from the chromosome 16p13.3 markers are shown below the symbols. The order of the seven markers analyzed is, from telomere (top) to centromere (bottom), D16S521, D16S3024, D16S3082, D16S3027, D16S423, D16S3030, and D16S3128. Blackened bars indicate the haplotype that cosegregates with the disease.

Figure 3

Ideogram of chromosome 16 and genetic map of markers used to delineate candidate region. The candidate region is shown as a blackened bar on the first vertical line, and the intermarker distances (in cM) are given. On the other vertical lines, blackened bars indicate those regions that cosegregate, and unblackened bars indicate regions that recombine and that therefore cannot contain the disease gene. The lines between rectangles indicate uninformative regions.