del Giudice E M, Santoro N, Cirillo G, D'Urso L, Di Toro R, Perrone L
Department of Pediatrics, Second University of Naples, Naples, Italy.
Diabetes. 2001 Sep;50(9):2157-60. doi: 10.2337/diabetes.50.9.2157.
Cocaine- and amphetamine-regulated transcript (CART) inhibits feeding and induces the expression of c-Fos in hypothalamic areas implicated in appetite regulation. Furthermore, the CART peptide is found in neurons regulating sympathetic outflow, which in turn play an integral role in regulating body temperature and energy expenditure. The CART gene was screened by single-strand conformation polymorphism and automatic sequencing in 130 (72 girls) unrelated obese Italian children and adolescents. Their Z-scores (mean +/- SD) of relative to BMI percentiles was 3.9 +/- 1.8, and the average age at obesity onset was 4.7 +/- 2.6 years. Two previously described silent polymorphisms were found in the 3' untranslated region: an adenine deletion at position 1457 in 9 patients (allele frequency 0.035) and an A/G substitution at position 1475 in 11 patients (allele frequency 0.042). We found no difference between the obese patients heterozygous for one of these polymorphisms and those patients homozygous for the wild allele with respect to their age of obesity onset, BMI Z-scores, and leptin levels. A missense mutation of G729C resulting in the substitution of Leu with Phe at codon 34, within the NH2-terminal CART region, has been detected in the heterozygous state in a 10-year-old obese boy who has been obese since the age of 2 years. The patient belongs to a large family of obese subjects. The mutation cosegregated with the severe obesity phenotype over three generations and was not found in the control population. Resting metabolic rates were lower than expected in the propositus (-14%) and his mother (-16%), who carried the mutation. Leucine at codon 34, conserved in this position in the human and in the rat sequences, immediately precedes a couple of lysine residues that may well represent a dibasic processing site. The Leu34Phe mutation might alter the susceptibility to proteolysis of this potential processing site, likely altering the CART effect on thermogenesis and energy expenditure.
可卡因和苯丙胺调节转录肽（CART）可抑制进食，并诱导参与食欲调节的下丘脑区域中c-Fos的表达。此外，CART肽存在于调节交感神经输出的神经元中，而交感神经输出在调节体温和能量消耗中起着不可或缺的作用。采用单链构象多态性和自动测序技术，对130名（72名女孩）无血缘关系的肥胖意大利儿童及青少年的CART基因进行了筛查。他们相对于BMI百分位数的Z值（均值±标准差）为3.9±1.8，肥胖起始的平均年龄为4.7±2.6岁。在3'非翻译区发现了两个先前描述的沉默多态性：9例患者在1457位有一个腺嘌呤缺失（等位基因频率0.035），11例患者在1475位有A/G替换（等位基因频率0.042）。我们发现，这些多态性之一的杂合肥胖患者与野生等位基因纯合患者在肥胖起始年龄、BMI Z值和瘦素水平方面没有差异。在一名自2岁起就肥胖的10岁肥胖男孩中，检测到了位于NH2末端CART区域内的错义突变G729C，该突变导致密码子34处的亮氨酸被苯丙氨酸取代。该患者来自一个肥胖受试者大家族。该突变在三代人中与严重肥胖表型共分离，在对照人群中未发现。先证者及其携带该突变的母亲的静息代谢率低于预期（分别低14%和16%）。密码子34处的亮氨酸在人类和大鼠序列的该位置保守，紧接在几个赖氨酸残基之前，这些赖氨酸残基很可能代表一个双碱性加工位点。Leu34Phe突变可能会改变这个潜在加工位点对蛋白水解的敏感性，很可能会改变CART对产热和能量消耗的作用。
