PDF(Pubmed)
Abstract：
LMX1B haploinsufficiency causes Nail-patella syndrome (NPS; MIM 161200), characterized by nail dysplasia, absent/hypoplastic patellae, chronic kidney disease, and glaucoma. Accordingly in mice, Lmx1b has been shown to play crucial roles in the development of the limb, kidney and eye. Although one functional allele of Lmx1b appears adequate for development, Lmx1b null mice display ventral-ventral distal limbs with abnormal kidney, eye and cerebellar development, more disruptive, but fully concordant with NPS. In Lmx1b functional knockouts (KOs), Lmx1b transcription in the limb is decreased nearly 6-fold, indicating autoregulation. Herein, we report on two conserved Lmx1b-associated cis-regulatory modules (LARM1 and LARM2) that are bound by Lmx1b, amplify Lmx1b expression with unique spatial modularity in the limb, and are necessary for Lmx1b-mediated limb dorsalization. These enhancers, being conserved across vertebrates (including coelacanth, but not other fish species), and required for normal locomotion, provide a unique opportunity to study the role of dorsalization in the fin to limb transition. We also report on two NPS patient families with normal LMX1B coding sequence, but with loss-of-function variations in the LARM1/2 region, stressing the role of regulatory modules in disease pathogenesis.
摘要：
LMX1B单倍功能不全导致甲髌骨综合征（NPS;MIM161200），以指甲发育不良为特征，髌骨缺失/发育不良，慢性肾病,和青光眼。因此，在小鼠中，Lmx1b已被证明在肢体的发育中起着至关重要的作用，肾脏和眼睛尽管Lmx1b的一个功能性等位基因似乎足以发育，Lmx1b空小鼠显示腹侧-腹侧远端肢体肾脏异常，眼睛和小脑发育，更具破坏性，但与NPS完全一致。在Lmx1b功能敲除(KOs)中，肢体中的Lmx1b转录减少了近6倍，指示自动调节。在这里，我们报告了由Lmx1b绑定的两个保守的Lmx1b相关的顺式调控模块(LARM1和LARM2)，在肢体中以独特的空间模块化扩增Lmx1b表达，并且是Lmx1b介导的肢体背行所必需的。这些增强剂,在脊椎动物(包括腔棘鱼，但不是其他鱼类)，并且是正常运动所必需的，提供了一个独特的机会来研究背孔在鳍到肢体过渡中的作用。我们还报道了两个具有正常LMX1B编码序列的NPS患者家庭，但随着LARM1/2区域功能丧失的变化，强调调节模块在疾病发病机理中的作用。
