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ptk7 mutant zebrafish models of congenital and idiopathic scoliosis implicate dysregulated Wnt signalling in disease

机译:先天性和特发性脊柱侧凸的ptk7突变斑马鱼模型暗示了疾病中Wnt信号的失调

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摘要

Scoliosis is a complex genetic disorder of the musculoskeletal system, characterized by three-dimensional rotation of the spine. Curvatures caused by malformed vertebrae (congenital scoliosis (CS)) are apparent at birth. Spinal curvatures with no underlying vertebral abnormality (idiopathic scoliosis (IS)) most commonly manifest during adolescence. The genetic and biological mechanisms responsible for IS remain poorly understood due largely to limited experimental models. Here we describe zygotic ptk7 (Zptk7) mutant zebrafish, deficient in a critical regulator of Wnt signalling, as the first genetically defined developmental model of IS. We identify a novel sequence variant within a single IS patient that disrupts PTK7 function, consistent with a role for dysregulated Wnt activity in disease pathogenesis. Furthermore, we demonstrate that embryonic loss-of-gene function in maternal-zygotic ptk7 mutants (MZptk7) leads to vertebral anomalies associated with CS. Our data suggest novel molecular origins of, and genetic links between, congenital and idiopathic forms of disease.
机译:脊柱侧弯是肌肉骨骼系统的复杂遗传疾病,其特征在于脊柱的三维旋转。畸形椎骨(先天性脊柱侧凸(CS))在出生时就很明显。没有潜在的椎体异常(特发性脊柱侧凸(IS))的脊柱弯曲最常见于青春期。很大程度上由于有限的实验模型,导致IS的遗传和生物学机制仍然知之甚少。在这里,我们将合子ptk7(Zptk7)突变斑马鱼描述为Wnt信号的关键调节因子,将其作为IS的第一个遗传定义的发育模型。我们在一个单一的IS患者中识别出一个新的序列变异体,该变异体会破坏PTK7功能,与疾病发病机理中Wnt活性失调的作用一致。此外,我们证明母体合子ptk7突变体(MZptk7)中的胚胎基因丧失功能导致与CS相关的椎骨异常。我们的数据表明先天性和特发性疾病的新的分子起源和遗传联系。

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