Deufel T, Golla A, Iles D, Meindl A, Meitinger T, Schindelhauer D, DeVries A, Pongratz D, MacLennan D H, Johnson K J
Kinderklinik im Dr. von Haunerschen Kinderspital, Kinderklinik der Universität München, Germany.
Am J Hum Genet. 1992 Jun;50(6):1151-61.
A locus for malignant hyperthermia susceptibility (MHS) has been localized on chromosome 19q12-13.2, while at the same time the gene encoding the skeletal muscle ryanodine receptor (RYR1) also has been mapped to this region and has been found to be tightly linked to MHS. RYR1 was consequently postulated as the candidate for the molecular defect causing MHS, and a point mutation in the gene has now been identified and is thought to be the cause of MH in at least some MHS patients. Here we report the results of a linkage study done with 19q12-13.2 markers, including the RYR1 cDNA, in two Bavarian families with MHS. In one of the families, three unambiguous recombination events between MHS and the RYR1 locus were found. In the second family only one informative meiosis was seen with RYR1. However, segregation analysis with markers for D19S75, D19S28, D19S47, CYP2A, BCL3, and APOC2 shows that the crossovers in the first family involve the entire haplotype defined by these markers flanking RYR1 and, furthermore, reveals multiple crossovers between these haplotypes and MHS in the second family. In these families, pairwise and multipoint lod scores below -2 exclude MHS from an interval spanning more than 26 cM and comprising the RYR1 and the previously described MHS locus. Our findings thus strongly suggest genetic heterogeneity of the MHS trait and prompt the search for another MHS locus.
恶性高热易感性（MHS）基因座已定位在19号染色体的19q12 - 13.2区域，与此同时，编码骨骼肌兰尼碱受体（RYR1）的基因也已定位到该区域，并且发现它与MHS紧密连锁。因此，RYR1被推测为导致MHS分子缺陷的候选基因，目前已在该基因中鉴定出一个点突变，并且认为它至少是部分MHS患者发生恶性高热（MH）的原因。在此，我们报告了在两个患有MHS的巴伐利亚家族中使用包括RYR1 cDNA在内的19q12 - 13.2标记进行连锁研究的结果。在其中一个家族中，发现MHS与RYR1基因座之间有三次明确的重组事件。在第二个家族中，仅观察到一次与RYR1相关的有信息减数分裂。然而，对D19S75、D19S28、D19S47、CYP2A、BCL3和APOC2标记的分离分析表明，第一个家族中的交叉涉及由RYR1两侧的这些标记定义的整个单倍型，此外，还揭示了第二个家族中这些单倍型与MHS之间的多次交叉。在这些家族中，低于 -2的成对和多点连锁值排除了MHS位于跨越超过26厘摩（cM）且包含RYR1和先前描述的MHS基因座的区间内。因此，我们的研究结果强烈提示MHS性状存在遗传异质性，并促使我们寻找另一个MHS基因座。
