Bénichou O, Cleiren E, Gram J, Bollerslev J, de Vernejoul M C, Van Hul W
Laboratoire INSERM U 349, Hôpital Lariboisière, Paris.
Am J Hum Genet. 2001 Sep;69(3):647-54. doi: 10.1086/323132. Epub 2001 Jul 23.
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.
骨硬化症是一组异质性疾病，其特征是由于骨吸收受损导致骨密度增加。除了两种或更多种常染色体隐性类型外，还描述了两种常染色体显性形式的骨硬化症，可通过临床和放射学体征进行区分。常染色体显性II型骨硬化症（ADO），也称为“阿尔伯斯-舍恩伯格病”，其特征为硬化，主要累及脊柱（椎体终板增厚，即鲁格-泽西脊柱）、骨盆（“骨中骨”结构）和颅底。这些患者的骨折率会升高。通过连锁分析，先前曾提示在1号染色体短臂2区1带存在一个导致II型ADO的基因。然而，对更多II型ADO家系的分析表明，II型ADO存在遗传异质性，1号染色体短臂2区1带位点只是一个次要位点。我们现在对一个患有II型ADO的法裔大家系进行全基因组连锁扫描，这使我们能够将II型ADO基因定位到16号染色体短臂1区3带。对另外五个患有II型ADO的家系中的微卫星标记进行分析，无法排除该染色体区域。标记D16S3027在重组率（θ值）为0时产生的最大对数优势（LOD）分数总和为12.70。根据家系中的关键重组体，可划定一个8.4厘摩的候选区域，其远端为标记D16S521，近端为标记D16S423。令人惊讶的是，所分析的家系之一是先前曾提示与1号染色体短臂2区1带连锁的丹麦家系。由于标记D16S3027在θ=0时产生的最大LOD分数为4.21，显然不能排除该家系与16号染色体短臂1区3带的连锁关系。因为目前没有其他患有II型ADO的家系被证明与1号染色体短臂2区1带连锁，所以我们认为该家系中致病基因最可能的定位是在16号染色体短臂1区3带。因此，这再次开启了由于16号染色体短臂1区3带上的单个基因导致II型ADO在遗传上具有同质性的可能性。
