Breakpoints around the HOXD cluster result in various limb malformations
Breakpoints around the HOXD cluster result in various limb malformations
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DOI：
10.1136/jmg.2005.033555
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发表时间：
2006-02-01
影响因子：
4
通讯作者：
Kalscheuer, VM
中科院分区：
文献类型：
--
作者：
Dlugaszewska, B;Silahtaroglu, A;Kalscheuer, VM
背景：描述疾病相关的平衡染色体重排是寻找候选基因和调控元件的一个有希望的起点。方法：我们鉴定并调查了3例涉及2q31染色体的肢体异常和断点患者。患者1伴有严重的短指和并指、智力低下、小脑发育不全、脊柱侧凸和肛门异位，携带平衡t(2; 10)（q31.1; q26.3）易位。患者2，易位t(2; 10)(q31.1; q23.33)，尺骨发育不全，桡骨缩短，手指异常，脊柱侧凸。患者3携带2号染色体近中心反转，inv(2)（p15q31）。其表型特征为双侧腓骨和桡骨发育不全，双侧尺骨发育不全，腕骨未僵化，双侧胫骨发育不全和脱位。结果：通过荧光原位杂交，我们已经将断点映射到大约170 kb或更小的间隔。这三个2q31断点都位于HOXD基因簇附近，它们都没有破坏任何已知的基因。结论：Hoxd基因在小鼠中的表达受顺式作用DNA元件的调控，其作用距离长达几百个碱基。此外，Hoxd基因在骨骼发育中起着既定的作用。因此，这三种重排很可能通过位置效应干扰了正常的HOXD基因调控。
Background: Characterisation of disease associated balanced chromosome rearrangements is a promising starting point in the search for candidate genes and regulatory elements.Methods: We have identified and investigated three patients with limb abnormalities and breakpoints involving chromosome 2q31. Patient 1 with severe brachydactyly and syndactyly, mental retardation, hypoplasia of the cerebellum, scoliosis, and ectopic anus, carries a balanced t( 2; 10)(q31.1; q26.3) translocation. Patient 2, with translocation t( 2; 10)( q31.1; q23.33), has aplasia of the ulna, shortening of the radius, finger anomalies, and scoliosis. Patient 3 carries a pericentric inversion of chromosome 2, inv( 2)( p15q31). Her phenotype is characterised by bilateral aplasia of the fibula and the radius, bilateral hypoplasia of the ulna, unossified carpal bones, and hypoplasia and dislocation of both tibiae.Results: By fluorescence in situ hybridisation, we have mapped the breakpoints to intervals of approximately 170 kb or less. None of the three 2q31 breakpoints, which all mapped close to the HOXD cluster, disrupted any known genes.Conclusions: Hoxd gene expression in the mouse is regulated by cis-acting DNA elements acting over distances of several hundred kilobases. Moreover, Hoxd genes play an established role in bone development. It is therefore very likely that the three rearrangements disturb normal HOXD gene regulation by position effects.