Larsson C, Shepherd J, Nakamura Y, Blomberg C, Weber G, Werelius B, Hayward N, Teh B, Tokino T, Seizinger B
Department of Clinical Genetics, Karolinska Hospital, Stockholm, Sweden.
J Clin Invest. 1992 Apr;89(4):1344-9. doi: 10.1172/JCI115720.
Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominantly inherited predisposition to neoplastic lesions of the parathyroids, pancreas, and the pituitary. We have previously located the predisposing genetic defect to the long arm of chromosome 11 by genetic linkage. In this study, 124 members of six MEN1 families, including 59 affected individuals, were genotyped for restriction fragment length polymorphisms with different DNA probes, and the genetic linkage between these marker systems and MEN1 was determined. 13 marker systems (17 DNA probes) were found to be linked to MEN1. These markers are located within a region on chromosome 11 spanning 14% meiotic recombinations, with the MEN1 locus in the middle. Four of the marker systems are on the centromeric side of MEN1, and four on the telomeric side, based on meiotic crossovers. The remaining five DNA probes are closely linked to MEN1, with no crossovers in our set of families. The 13 marker systems can be used for an accurate and reliable premorbid test for MEN1. In most clinical situations it is possible to identify a haplotype of this part of chromosome 11 with the mutant MEN1 allele in the middle. The calculated predictive accuracy is greater than 99.5% if three such marker systems are informative. Therefore, genetic linkage testing can be used for informed genetic counseling in MEN1 families, and to avoid unnecessary biochemical screening programs.
1型多发性内分泌腺瘤病（MEN1）是一种常染色体显性遗传疾病，易引发甲状旁腺、胰腺和垂体的肿瘤性病变。我们之前通过基因连锁分析将致病基因缺陷定位到了11号染色体长臂上。在本研究中，对6个MEN1家族的124名成员（包括59名患病个体）进行了基因分型，使用不同的DNA探针检测限制性片段长度多态性，并确定这些标记系统与MEN1之间的基因连锁关系。发现13个标记系统（17个DNA探针）与MEN1连锁。这些标记位于11号染色体上一个跨度为14%减数分裂重组的区域内，MEN1基因座位于中间。根据减数分裂交叉情况，其中4个标记系统位于MEN1的着丝粒侧，4个位于端粒侧。其余5个DNA探针与MEN1紧密连锁，在我们的家系中未出现交叉情况。这13个标记系统可用于对MEN1进行准确可靠的病前检测。在大多数临床情况下，有可能识别出11号染色体这一部分的单倍型，中间带有突变的MEN1等位基因。如果三个这样的标记系统具有信息性，计算得出的预测准确率大于99.5%。因此，基因连锁检测可用于为MEN1家族提供知情的遗传咨询，并避免不必要的生化筛查程序。
