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Localization of a gene for autosomal dominant osteopetrosis (Albers-Schonberg 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.

SUBMITTER: Van Hul W

PROVIDER: S-EPMC1715917 | biostudies-other | 1997 Aug

REPOSITORIES: biostudies-other

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Localization of a gene for autosomal dominant osteopetrosis (Albers-Schönberg disease) to chromosome 1p21.

Van Hul W W Bollerslev J J Gram J J Van Hul E E Wuyts W W Benichou O O Vanhoenacker F F Willems P J PJ

American journal of human genetics 19970801 2

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 chromoso ...[more]

PMID: 9311741

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Project description: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.

Dataset Information

Localization of a gene for autosomal dominant osteopetrosis (Albers-Schonberg disease) to chromosome 1p21.

Publications

Localization of a gene for autosomal dominant osteopetrosis (Albers-Schönberg disease) to chromosome 1p21.

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