羅素–西弗氏症與人類印記基因甲基化的定量與探討

Abstract

中文摘要實驗主要在探討H19/IGF2區域低度甲基化的情形，與羅素–西弗氏症(Russell–Silver syndrome; RSS)患者臨床表徵間的關聯性。SS為一種罕見的先天性遺傳疾病，其特徵有出生前子宮內生長遲滯(intrauterine growth retardation; IUGR)、出生後生長遲緩(Lack of postnatal catch-up growth)、倒三角臉(Triangular face)、身體左右不對稱(Asymmetry)及第五根手指彎斜向內(clinodactyly)等主要特徵，並可能伴隨發展遲緩(Developmental delay)、語言障礙(Delayed speech)、餵食困難(Feeding difficulties)、身體出現咖啡牛奶色斑(Café au lait spots)、肌肉張力低(Muscular hypotonial)、低血糖(Hypoglycemia)等次要特徵，臨床特徵歧異性高。據目前研究結果發現，RSS的遺傳模式及病因學複雜且多樣化，多數個案為家族中首例。在病因學方面，除了染色體構造及數目異常外，近年來研究顯示可能與部分基因的甲基化程度有關，其中約7~10%的RSS病患為第七對染色體母源單親二體症(matUPD7)、部分患者為7號染色體鑲嵌型不平衡轉位(mUPD7q31-qter)以及可能因第11對染色體上的H19促進子(promoter)發生低度甲基化的情形造成，近年來研究發現約有50%左右的患者在H19/IGF2區域間甲基化程度有偏低的現象。本實驗針對二十八位具有RSS臨床表徵的病患(五項主要特徵中符合其中三項，並伴有一項次要特徵)，在我們所選定的H19與IGF2基因上游促進子的位置進行人類印記基因(imprinting genes)甲基化程度的檢測，發現七名病患在H19促進子區域有低度甲基化的情形(25%)，而H19與IGF2促進子區域甲基化的程度呈弱相關(R=0.539)。就RSS病人而言， H19區域有低甲基化的患者其臨床表徵在相對正常頭圍的情況與一般RSS患者相比有較高的發生機率。我們的研究顯示IGF2-H19區域的低甲基化對於RSS而言是個主要的致病原因。若將診斷標準定義的更嚴格，以同時具有IUGR及出生後生長發育不良做為RSS患者的必要條件時，則我們所選定的患者中有五位會被歸類於似RSS表徵的患者(SRS-like syndrome)，並且在計算RSS患者低度甲基化的比率上會提高(30.4%)，但在相對正常頭圍的分析上與前述結果無異。一些相關報導中發現IGF2/H19低度甲基化的情況會發生在RSS及似RSS表徵的患者身上，此發現可能對於將來在研究生長遲緩等相關研究上至觀重要。而此區域低甲基化患者的臨床特色，亦可提供醫師疾病診斷時之參考。

Abstractypomethylation of the IGF2/H19 locus is associated with a severe phenotype in Silver-Russell syndrome.ussell-Silver syndrome (RSS) is a rare congenital disorder.The major characteristic of RSS include intrauterine growth retardation (IUGR) , lack of postnatal catch-up growth, triangular face, body asymmetry and 5th finger clinodactylyand.Affected individuals may also have diverse symptoms such as developmental delay, delayed speech, feeding difficulties, café au lait spots, muscular hypotonial and hypoglycemia.The clinical picture is extremely diverse.ecently finding,the mode of inheritance is variable with sporadic cases also being described.The etiology of RSS is heterogeneous, but recently hypomethylation of the IGH2/H19 locus is known to explain 50% of the cases. We analyzed 28 patients who fitted in three or more of the five criteria for RSS (IUGR, lack of catch-up growth, characteristic face, asymmetry, and 5th finger clinodactyly). We identified H19 hypomethylation in 7 cases (25%). H19 hypomethylation was correlated to the methylation status of the IGF2 control region. Phenotype analysis revealed a high incidence of preservation of head circumference in cases with IGF2/H19 hypomethylation. When we employed a stricter diagnostic criteria that both IUGR and lack of catch-up growth being essential, a portion of the cases were classified into the SRS-like syndrome, but the percentage of IGF2/H19 hypomethylation in SRS became higher. IGF2/H19 hypomethylation occurred in both RSS and RSS-like syndromes in this study. These materials will be crucial in future researches on the growth retardation syndromes.