Wu Y Q, Heutink P, de Vries B B, Sandkuijl L A, van den Ouweland A M, Niermeijer M F, Galjaard H, Reyniers E, Willems P J, Halley D J
Department of Clinical Genetics, Erasmus University, Rotterdam, The Netherlands.
Hum Mol Genet. 1994 Jan;3(1):167-71. doi: 10.1093/hmg/3.1.167.
Hereditary multiple exostoses (EXT) is an autosomal dominant disorder of enchondral bone formation characterized by multiple bony outgrowths (exostoses), with progression to osteosarcoma in a minority of cases. The exclusive involvement of skeletal abnormalities distinguishes EXT from the clinically more complex Langer-Giedion syndrome (LGS), which is associated with deletions at chromosome 8q24. Previously, linkage analysis has revealed a locus for EXT in the LGS region on chromosome 8q24. However, locus heterogeneity was apparent with 30% of the families being unlinked to 8q24. We report on two large pedigrees segregating EXT in which linkage to the LGS region was excluded. To localize the EXT gene(s) in these families we performed a genome search including 254 microsatellite markers dispersed over all autosomes and the X chromosome. In both families evidence was obtained for linkage to markers from the proximal short and long arms of chromosome 11. Two-point analysis gave the highest lod score for D11S554 (Zmax = 7.148 at theta = 0.03). Multipoint analysis indicated a map position for the EXT gene between D11S905 and D11S916, with a peak multipoint lod score of 8.10 at 6 cM from D11S935. The assignment of a second locus for EXT to the pericentromeric region of chromosome 11 implicates an area that is particularly rich in genes responsible for developmental abnormalities and neoplasia.
遗传性多发性骨软骨瘤（EXT）是一种常染色体显性遗传性软骨内成骨障碍疾病，其特征为多发性骨赘（骨软骨瘤），少数病例会进展为骨肉瘤。骨骼异常的单独出现将EXT与临床更为复杂的朗格-吉迪恩综合征（LGS）区分开来，后者与8号染色体q24区域的缺失有关。此前，连锁分析已揭示8号染色体q24区域的LGS区内存在EXT的一个基因座。然而，基因座异质性很明显，30%的家族与8q24不连锁。我们报告了两个分离EXT的大家系，其中排除了与LGS区域的连锁关系。为了在这些家族中定位EXT基因，我们进行了全基因组搜索，包括分布在所有常染色体和X染色体上的254个微卫星标记。在两个家族中均获得了与11号染色体近端短臂和长臂上的标记连锁的证据。两点分析得出D11S554的最高连锁对数分数（在θ = 0.03时Zmax = 7.148）。多点分析表明EXT基因的图谱位置在D11S905和D11S916之间，距D11S935 6厘摩处的最高多点连锁对数分数为8.10。将EXT的第二个基因座定位于11号染色体的着丝粒周围区域，这意味着该区域特别富含负责发育异常和肿瘤形成的基因。
