Miraglia del Giudice E, Cirillo G, Santoro N, D'Urso L, Carbone M T, Di Toro R, Perrone L
Department of Pediatrics, Second University of Naples, Via S.Andrea delle Dame no. 4, 80138 Napoli, Italy.
Int J Obes Relat Metab Disord. 2001 Jan;25(1):61-7. doi: 10.1038/sj.ijo.0801485.
Although linkage studies strongly suggest that proopiomelanocortin (POMC) alterations could play a role in the genetic predisposition to obesity, systematic POMC mutational analysis did not completely confirm this hypothesis.
To verify the presence of mutations of the POMC coding region in Italian children with very early onset obesity.
Eighty seven unrelated Italian obese children and adolescents were studied. Mean age at obesity onset was 4.7+/-2.5 y. The POMC gene coding region was screened using single-strand conformation polymorphism (SSCP) analysis. Bi-directional automatic sequencing of PCR products was performed for all individuals who showed an aberrant SSCP pattern.
Three new mutations have been identified in the heterozygous state in three patients: (a) G3834C, resulting in the substitution of Ser with Thr at codon 7 within the POMC signal peptide; (b) C3840T, resulting in the substitution of Ser with Leu at codon 9 of the pre-proopiomelanocortin signal peptide; and (c) C7406G, producing the substitution of Arg with Gly at codon 236 within the beta-endorphin peptide. A polymorphism consisting of a 9 bp insertion, AGC AGC CGC, between position 6997 and 6998 has been found at the heterozygous state in nine patients. They showed leptin levels adjusted for BMI, gender and pubertal stage significantly higher than obese subjects homozyous for the POMC wild-type allele.
Mutations in codons 7 and 9 of the signal peptide may alter the translocation of the pre-proopiomelanocortin into the endoplasmic reticulum and, therefore, can be implicated in obesity. Although further studies are required, the polymorphism between position 6997 and 6998 may represent one of the genetic variations that explain the linkage between obesity and POMC. International Journal of Obesity (2001) 25, 61-67
尽管连锁研究强烈提示阿片促黑激素皮质素原（POMC）改变可能在肥胖的遗传易感性中起作用，但系统的POMC突变分析并未完全证实这一假说。
验证极早发肥胖的意大利儿童中POMC编码区是否存在突变。
研究了87名无亲缘关系的意大利肥胖儿童和青少年。肥胖发病的平均年龄为4.7±2.5岁。采用单链构象多态性（SSCP）分析筛查POMC基因编码区。对所有显示异常SSCP模式的个体进行PCR产物的双向自动测序。
在3例患者中以杂合状态鉴定出3个新突变：（a）G3834C，导致POMC信号肽内第7密码子的丝氨酸被苏氨酸取代；（b）C3840T，导致阿片促黑激素皮质素原前体信号肽第9密码子的丝氨酸被亮氨酸取代；（c）C7406G，导致β-内啡肽肽内第236密码子的精氨酸被甘氨酸取代。在9例患者中以杂合状态发现了一个由6997位和6998位之间9 bp插入（AGC AGC CGC）组成的多态性。他们经体重指数、性别和青春期阶段校正后的瘦素水平显著高于POMC野生型等位基因纯合的肥胖受试者。
信号肽第7和第9密码子的突变可能改变阿片促黑激素皮质素原前体向内质网的转运，因此可能与肥胖有关。尽管需要进一步研究，但6997位和6998位之间的多态性可能是解释肥胖与POMC之间连锁关系的遗传变异之一。《国际肥胖杂志》（2001年）25卷，61 - 67页
