近日,一个由英美科学家组成的研究小组在《自然—遗传学》(Nature Genetics)上发表最新研究论文称,他们发现一种罕见基因变异,会驱动细胞过度生长,从而导致身体某一部分过度肥大。
研究人员在对一位双腿异常肥大的病患进行基因分析后发现,磷脂酰肌酸3激酶(PI3K)信号通路内的基因变异,可能是导致该病患双腿异常肥大的罪魁祸首。这一变异会导致PI3K过度活跃,促使细胞过度生长。研究人员随后通过对9位类似患者的基因分析,最终证实了他们的推论。
该类变异主要发生在胎儿发育期间。与普通基因变异会影响全身细胞不同,这种变异只会影响变异发生区域的细胞,这也是为什么病患只是身体某一部分而非全身肥大的原因。
研究人员指出,这一突变基因是一个新的药物标靶,藉此开发出安全长效的药物,将有助于治疗身体部分肥大这一罕见病症。(生物谷Bioon.com)
doi:10.1038/ng.2332
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osaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA
Marjorie J Lindhurst,1, 16 Victoria E R Parker,2, 16 Felicity Payne,3 Julie C Sapp,1 Simon Rudge,4 Julie Harris,2 Alison M Witkowski,1 Qifeng Zhang,4 Matthijs P Groeneveld,2 Carol E Scott,3 Allan Daly,3 Susan M Huson,5 Laura L Tosi,6 Michael L Cunningham,7 Thomas N Darling,8 Joseph Geer,9 Zoran Gucev,10 V Reid Sutton,11 Christos Tziotzios,12 Adrian K Dixon,13 Timothy Helliwell,14 Stephen O'Rahilly,2, 15 David B Savage,2, 15 Michael J O Wakelam,4 Inês Barroso,2, 3
The phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway is critical for cellular growth and metabolism. Correspondingly, loss of function of PTEN, a negative regulator of PI3K, or activating mutations in AKT1, AKT2 or AKT3 have been found in distinct disorders featuring overgrowth or hypoglycemia. We performed exome sequencing of DNA from unaffected and affected cells from an individual with an unclassified syndrome of congenital progressive segmental overgrowth of fibrous and adipose tissue and bone and identified the cancer-associated mutation encoding p.His1047Leu in PIK3CA, the gene that encodes the p110α catalytic subunit of PI3K, only in affected cells. Sequencing of PIK3CA in ten additional individuals with overlapping syndromes identified either the p.His1047Leu alteration or a second cancer-associated alteration, p.His1047Arg, in nine cases. Affected dermal fibroblasts showed enhanced basal and epidermal growth factor (EGF)-stimulated phosphatidylinositol 3,4,5-trisphosphate (PIP3) generation and concomitant activation of downstream signaling relative to their unaffected counterparts. Our findings characterize a distinct overgrowth syndrome, biochemically demonstrate activation of PI3K signaling and thereby identify a rational therapeutic target.