Sudbrak R, Procaccio V, Klausnitzer M, Curran J L, Monsieurs K, van Broeckhoven C, Ellis R, Heyetens L, Hartung E J, Kozak-Ribbens G
Stoffwechsellabor, Klinik und Poliklinik für Kinderheilkunde, Universität Münster, Germany.
Am J Hum Genet. 1995 Mar;56(3):684-91.
Malignant hyperthermia (MH) is a potentially lethal pharmacogenetic disease for which MH susceptibility (MHS) is transmitted as an autosomal dominant trait. A potentially life-threatening MH crisis is triggered by exposure to commonly used inhalational anesthetics and depolarizing muscle relaxants. The first malignant hyperthermia susceptibility locus (MHS1) was identified on human chromosome 19q13.1, and evidence has been obtained that defects in the gene for the calcium-release channel of skeletal muscle sarcoplasmic reticulum (ryanodine receptor; RYR1) can cause some forms of MH. However, MH has been shown to be genetically heterogeneous, and additional loci on chromosomes 17q and 7q have been suggested. In a collaborative search of the human genome with polymorphic microsatellite markers, we now found linkage of the MHS phenotype, as assessed by the European in vitro contracture test protocol, to markers defining a 1-cM interval on chromosome 3q13.1. A maximum multipoint lod score of 3.22 was obtained in a single German pedigree with classical MH, and none of the other pedigrees investigated in this study showed linkage to this region. Linkage to both MHS1/RYR1 and putative loci on chromosome 17q and 7q were excluded. This study supports the view that considerable genetic heterogeneity exists in MH.
恶性高热(MH)是一种潜在致命的药物遗传疾病,其中恶性高热易感性(MHS)作为常染色体显性性状遗传。接触常用的吸入性麻醉剂和去极化肌肉松弛剂会引发潜在危及生命的恶性高热危机。首个恶性高热易感性基因座(MHS1)在人类19号染色体q13.1上被确定,并且已获得证据表明骨骼肌肌浆网钙释放通道(兰尼碱受体;RYR1)基因缺陷可导致某些形式的恶性高热。然而,恶性高热已被证明具有遗传异质性,并且有人提出在17号染色体q和7号染色体q上存在其他基因座。在一项使用多态性微卫星标记对人类基因组进行的合作研究中,我们现在发现,按照欧洲体外挛缩试验方案评估,MHS表型与定义3号染色体q13.1上一个1厘摩区间的标记存在连锁关系。在一个患有典型恶性高热的德国单一家系中获得了最大多点对数优势分数3.22,并且本研究中调查的其他家系均未显示与该区域存在连锁关系。与MHS1/RYR1以及17号染色体q和7号染色体q上的假定基因座的连锁关系均被排除。本研究支持恶性高热存在相当大的遗传异质性这一观点。