人類(lèi)家族性A1型短指(趾)癥,,是遺傳疾病的百年之謎,。經(jīng)過(guò)長(zhǎng)達(dá)8年艱苦鉆研,,上海交通大學(xué)賀林院士領(lǐng)銜的科研團(tuán)隊(duì)成功揭示了該癥的致病機(jī)理。國(guó)際權(quán)威雜志《自然》在今天(北京時(shí)間3月2日)凌晨發(fā)布的最新一期期刊上,,發(fā)表了賀林科研團(tuán)隊(duì)的研究論文《IHH基因點(diǎn)突變通過(guò)改變IHH蛋白信號(hào)能力和信號(hào)距離導(dǎo)致指(趾)畸形》,,完美地講述了A1型短指(趾)癥的百年故事。
人類(lèi)家族性A1型短指(趾)癥,,是1903年發(fā)現(xiàn)的第一例符合孟德?tīng)栠z傳規(guī)律的常染色體顯性遺傳病,,主要表現(xiàn)為患者的中間指(趾)節(jié)縮短,甚至與遠(yuǎn)端指(趾)節(jié)融合,。該病長(zhǎng)期以來(lái)作為典型案例出現(xiàn)在各國(guó)遺傳學(xué)和生物學(xué)教科書(shū)中,,世界各國(guó)科學(xué)家都在根據(jù)自己掌握的病例家系尋找致病基因,卻屢遭失敗,。參與競(jìng)爭(zhēng)行列的賀林科研團(tuán)隊(duì),,8年前首次發(fā)現(xiàn)A1型短指(趾)癥致病基因——IHH基因后,此番再次取得重要成果,,最終成功揭開(kāi)了遺傳疾病的百年之謎,。
早在2000年,賀林教授就帶領(lǐng)當(dāng)時(shí)的上海交通大學(xué)/中國(guó)科學(xué)院上海生命科學(xué)研究院“神經(jīng)精神病和人類(lèi)遺傳學(xué)聯(lián)合研究室”,,把A1型短指(趾)癥致病基因定位于2號(hào)染色體長(zhǎng)臂的特定區(qū)域,,這為致病基因的確定打下了堅(jiān)實(shí)基礎(chǔ),該項(xiàng)成果于當(dāng)年發(fā)表在《美國(guó)人類(lèi)遺傳學(xué)》上,。2001年,,研究進(jìn)一步深入,發(fā)現(xiàn)并克隆了導(dǎo)致A1型短指(趾)癥的IHH基因,,首次將IHH基因控制骨骼發(fā)育的動(dòng)物研究結(jié)論延伸到了人類(lèi),,并發(fā)現(xiàn)了該基因的點(diǎn)突變直接導(dǎo)致人類(lèi)骨骼疾病,。成果被《自然遺傳學(xué)》雜志發(fā)表,對(duì)遺傳生物學(xué)界影響廣泛,。
這次最終揭示A1型短指(趾)癥致病機(jī)理的研究,,由賀林科研團(tuán)隊(duì)與香港大學(xué)等密切合作,科研人員通過(guò)對(duì)短指(趾)小鼠模型的“體內(nèi)”和細(xì)胞的“體外”研究,,發(fā)現(xiàn)了A1型短指(趾)癥致病基因IHH的點(diǎn)突變,,造成骨骼組織中Hedgehog信號(hào)能力和信號(hào)范圍發(fā)生改變,最終導(dǎo)致中間指(趾)節(jié)的嚴(yán)重縮短甚至消失,。研究成果不僅清晰地闡述了A1型短指(趾)癥發(fā)生的分子機(jī)制,,而且發(fā)現(xiàn)IHH基因可能參與指骨的早期發(fā)育調(diào)控,開(kāi)拓了IHH基因在骨骼生長(zhǎng)發(fā)育中新的角色,,為現(xiàn)代遺傳發(fā)育生物學(xué)增添新的內(nèi)容,,對(duì)肢體和骨骼發(fā)育生物學(xué)有著重要的意義,也為相關(guān)骨骼疾病的科學(xué)研究和臨床診斷提供了有力依據(jù),。
由此,,A1型短指(趾)癥的研究經(jīng)歷了最初致病基因的定位、找尋,、確定,、克隆,到最后致病機(jī)理得到闡述,,完整地解答了一個(gè)遺傳疾病的百年之謎,。
耐得寂寞,持之以恒,,是賀林院士領(lǐng)銜科研團(tuán)隊(duì)最終摘得科研成果的關(guān)鍵,。據(jù)悉,賀林院士在基因定位成果發(fā)表前,,就已開(kāi)始尋找和克隆基因的工作,;在基因克隆相關(guān)的成果發(fā)表前,他便踏上了研究致病機(jī)理的征程,。當(dāng)時(shí)正處于人類(lèi)基因組計(jì)劃即將完成之際,,人們對(duì)基因功能的大范圍研究剛剛起步,內(nèi)地還不具備進(jìn)行小鼠模型研究的能力,。于是,,賀林院士的團(tuán)隊(duì)在世界范圍內(nèi)搜索研究骨骼功能的課題組,在考慮盡可能使知識(shí)產(chǎn)權(quán)中國(guó)化和交流便捷等因素之后,,把合作對(duì)象鎖定在香港大學(xué),。賀林院士派上海交通大學(xué)Bio-X中心兩位研究生高波和胡建新前往香港,作為核心力量開(kāi)展動(dòng)物模型的“體內(nèi)”研究,。同時(shí)在上海交大組織另一支科研隊(duì)伍,,開(kāi)展細(xì)胞“體外”研究,。一內(nèi)一外,相互配合,,一干就是8年,。(生物谷Bioon.com)
生物谷推薦原始出處:
Nature advance online publication 1 March 2009 | doi:10.1038/nature07862
A mutation in Ihh that causes digit abnormalities alters its signalling capacity and range
Bo Gao1,2,10, Jianxin Hu1,2,10, Sigmar Stricker3,4, Martin Cheung1,5, Gang Ma2, Kit Fong Law1, Florian Witte3,4,6, James Briscoe7, Stefan Mundlos3,4, Lin He2,8,9, Kathryn S. E. Cheah1,5 & Danny Chan1,5
1 Department of Biochemistry, the University of Hong Kong, Hong Kong, China
2 Bio-X Center, Shanghai Jiao Tong University, 1954 Huashan Road, Shanghai 200030, China
3 Max-Planck Institute for Molecular Genetics, Ihnestrasse 73, 14195 Berlin, Germany
4 Institut für Medizinische Genetik, Charité, Universit?tsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
5 Centre for Reproduction, Development and Growth, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China
6 Institute for Chemistry/Biochemistry, Free University Berlin, Thielallee 63, 14195 Berlin, Germany
7 Developmental Neurobiology, National Institute for Medical Research, Mill Hill, London NW7 1AA, UK
8 Institute for Nutritional Sciences, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
9 Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
10 These authors contributed equally to this work.
Brachydactyly type A1 (BDA1) was the first recorded disorder of the autosomal dominant Mendelian trait in humans, characterized by shortened or absent middle phalanges in digits. It is associated with heterozygous missense mutations in indian hedgehog (IHH)1, 2. Hedgehog proteins are important morphogens for a wide range of developmental processes3, 4. The capacity and range of signalling is thought to be regulated by its interaction with the receptor PTCH1 and antagonist HIP1. Here we show that a BDA1 mutation (E95K) in Ihh impairs the interaction of IHH with PTCH1 and HIP1. This is consistent with a recent paper showing that BDA1 mutations cluster in a calcium-binding site essential for the interaction with its receptor and cell-surface partners5. Furthermore, we show that in a mouse model that recapitulates the E95K mutation, there is a change in the potency and range of signalling. The mice have digit abnormalities consistent with the human disorder.