Circadian rhythm abnormalities of melatonin in Smith-Magenis syndrome
Circadian rhythm abnormalities of melatonin in Smith-Magenis syndrome
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DOI：
10.1136/jmg.37.6.428
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发表时间：
2000-06-01
影响因子：
4
通讯作者：
Lupski, JR
中科院分区：
文献类型：
--
作者：
Potocki, L;Glaze, D;Lupski, JR
背景-Smith-Magenis综合征(SMS)是一种与17号染色体p11.2带半合缺失相关的多发性先天性异常/智力低下综合征。特征特征包括神经行为异常，如攻击性和自残行为，以及严重的睡眠障碍。大多数患者都有一个常见的缺失，其特征是在分子水平上。物理作图研究表明，所有具有共同缺失的患者都是COP9信号体3亚单位(COPS3)的单倍体不足，COPS3在植物和人类之间是保守的，在植物中拟南芥调节基因转录对光的响应。这一基因的单倍性不足被认为可能与这些患者的睡眠障碍有关。褪黑素是一种由松果体分泌的激素。据报道，当夜间服用这种睡眠诱导激素时，短信患者的睡眠障碍较少。方法：结合28例短信患者的24小时睡眠研究，测定了19例短信患者尿液中褪黑素的主要肝脏代谢物6-硫代谢素(AMT6s)的排泄量。28例患者中有5例没有常见的短信缺失。为了研究COPS3单倍体功能不全与褪黑素分泌紊乱的潜在相关性，我们用两个含有COPS3编码外显子的BAC进行了荧光原位杂交(FISH)。除1例外，其余患者均观察到aMT6s昼夜节律异常。有趣的是，这位患者没有常见的缺失。所有被研究的患者，包括一名褪黑激素节律正常的患者，COPS3单倍体不足。结论--我们的数据表明褪黑激素昼夜节律紊乱，证明Smith-Magenis综合征的睡眠模式紊乱。我们的发现表明，褪黑激素昼夜节律的异常和睡眠模式的改变可能是褪黑素的产生、分泌、分布或代谢异常的继发因素；然而，COPS3的直接作用尚不能确定。
Background-Smith-Magenis syndrome (SMS) is a multiple congenital anomalies/mental retardation syndrome associated with a hemizygous deletion of chromosome 17, band p11.2. Characteristic features include neurobehavioural abnormalities such as aggressive and self-injurious behaviour and significant sleep disturbances. The majority of patients have a common deletion characterised at the molecular level. Physical mapping studies indicate that all patients with the common deletion are haploinsufficient for subunit 3 of the COP9 signalosome (COPS3), which is conserved from plants to humans, and in the plant Arabidopis thaliana regulates gene transcription in response to light. Haploinsufficiency of this gene is hypothesised to be potentially involved in the sleep disturbances seen in these patients. Melatonin is a hormone secreted by the pineal gland. SMS patients are reported to have fewer sleep disturbances when given a night time dose of this sleep inducing hormone.Methods-Urinary excretion of 6-sulphatoxymelatonin (aMT6s), the major hepatic metabolite of melatonin, in 19 SMS patients were measured in conjunction with 24 hour sleep studies in 28 SMS patients. Five of the 28 patients did not have the common SMS deletion. To investigate a potential correlation of COPS3 haploinsufficiency and disturbed melatonin excretion, we performed fluorescence in situ hybridisation (FISH) using two BACs containing coding exons of COPS3.Results-All SMS patients show significant sleep disturbances when assessed by objective criteria. Abnormalities in the circadian rhythm of aMT6s were observed in all but one SMS patient. Interestingly this patient did not have the common deletion. All patients studied, including the one patient with a normal melatonin rhythm, were haploinsufficient for COPS3.Conclusions-Our data indicate a disturbed circadian rhythm in melatonin and document the disturbed sleep pattern in Smith-Magenis syndrome. Our findings suggest that the abnormalities in the circadian rhythm of melatonin and altered sleep patterns could be secondary to aberrations in the production, secretion, distribution, or metabolism of melatonin; however, a direct role for COPS3 could not be established.