近日，一個(gè)由英美科學(xué)家組成的研究小組在《自然—遺傳學(xué)》（Nature Genetics）上發(fā)表最新研究論文稱，他們發(fā)現(xiàn)一種罕見基因變異，會(huì)驅(qū)動(dòng)細(xì)胞過(guò)度生長(zhǎng)，從而導(dǎo)致身體某一部分過(guò)度肥大。
研究人員在對(duì)一位雙腿異常肥大的病患進(jìn)行基因分析后發(fā)現(xiàn),，磷脂酰肌酸3激酶（PI3K）信號(hào)通路內(nèi)的基因變異，可能是導(dǎo)致該病患雙腿異常肥大的罪魁禍?zhǔn)?。這一變異會(huì)導(dǎo)致PI3K過(guò)度活躍,，促使細(xì)胞過(guò)度生長(zhǎng)。研究人員隨后通過(guò)對(duì)9位類似患者的基因分析,，最終證實(shí)了他們的推論,。
該類變異主要發(fā)生在胎兒發(fā)育期間。與普通基因變異會(huì)影響全身細(xì)胞不同,，這種變異只會(huì)影響變異發(fā)生區(qū)域的細(xì)胞,，這也是為什么病患只是身體某一部分而非全身肥大的原因。
研究人員指出,，這一突變基因是一個(gè)新的藥物標(biāo)靶,，藉此開發(fā)出安全長(zhǎng)效的藥物，將有助于治療身體部分肥大這一罕見病癥,。（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.
