MOLECULAR GENETIC-EVIDENCE FOR HETEROGENEITY IN MANIC-DEPRESSION
MOLECULAR GENETIC-EVIDENCE FOR HETEROGENEITY IN MANIC-DEPRESSION
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DOI：
10.1038/325805a0
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发表时间：
1987-02-26
期刊：
影响因子：
64.8
通讯作者：
BRYNJOLFSSON, J
中科院分区：
文献类型：
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作者：
HODGKINSON, S;SHERRINGTON, R;BRYNJOLFSSON, J
躁狂抑郁症是一种严重的周期性精神疾病1，2，可以是单极或双极，在大多数人群中的终生风险约为7/1，000 3。有多个躁狂抑郁症病例的家庭已经被描述为与常染色体显性遗传和X连锁遗传传播模式兼容2，4-6。有助于改善抑郁症和躁狂症的精神活性抗抑郁药和兴奋剂药物被认为是通过影响儿茶酚胺神经递质系统，如肾上腺素，去甲肾上腺素和多巴胺等7。影响酪氨酸羟化酶（TH）基因的突变8，9，编码限速酶的合成，这三个neurontransmitters 7，因此可能是负责引起躁狂抑郁症表型。我们已经研究了三个冰岛的kinesia其中似乎是一个单一的常染色体显性遗传病等位基因分离。在这些家庭中，73人中有44人处于危险之中。利用编码酪氨酸羟化酶8，9、Harvey-ras-1可变区（HRAS 1）10和胰岛素基因可变区（INS）11的克隆进行遗传连锁研究。所有三个标记都在11号染色体上紧密连锁（参考文献12），并用于观察三个受影响的激酶中限制性片段长度多态性（RFLP）的分离。我们在这三个家庭中没有发现与这些标记相关的证据。与此相反，Gerhardet等人在一个单一的阿米什人大家族中发现了躁狂抑郁症和HRAS 1之间的联系。我们的结论是，有遗传异质性的连锁躁狂抑郁症。因此，在不同的基因座突变负责躁狂抑郁症表型在阿米什人和冰岛。
Manic depression is a severe cyclic mental illness1,2that can be unipolar or bipolar and has a lifetime risk of approximately 7 per 1,000 in most populations3. Families with multiple cases of manic depression have been described that are compatible with both autosomal dominant and X-linked modes of genetic transmission2,4–6. Psychoactive antidepressant and stimulant drugs that help to ameliorate depression and mania are thought to act by affecting catecholamine neurotransmitter systems such as adrenaline, noradrenaline and dopamine, amongst others7. Mutations affecting the tyrosine hydroxylase (TH) gene8,9, which encodes the rate-limiting enzyme for the synthesis of these three neurotransmitters7, might therefore be responsible for causing the manic depressive phenotype. We have studied three Icelandic kindreds amongst whom it appears that a single autosomal dominant disease allele is segregating. In these families there were 44 cases amongst 73 individuals at risk. Genetic linkage studies were carried out using clones encoding tyrosine hydroxylase8,9the variable portion of the Harvey-ras-1 (HRAS1)10locus and the variable region of the insulin gene (INS)11. All three markers are closely linked on chromosome 11 (ref. 12) and were used to observe the segregation of restriction fragment length polymorphisms (RFLPs) in the three affected kindreds. We found no evidence for linkage to these markers in any of the three families. In contrast, Gerhardet al.13–15found linkage between manic depression andHRAS1in a single large Amish kindred. We conclude that there is genetic heterogeneity of linkage in manic depression. Therefore mutations at different loci are responsible for the manic depressive phentoype in the Amish and in Iceland.