The Mutational Landscape of PTK7 in Congenital Scoliosis and Adolescent Idiopathic Scoliosis.

Zhe Su,Hengqiang Zhao,Sen Zhao,Yuchen Niu,Nan Wu,Terry Jianguo Zhang,Shengru Wang,Yang Yang,Zhihong Wu,Xiaoxin Li,Guixing Qiu

doi:10.3390/genes12111791

Abstract

Depletion of ptk7 is associated with both congenital scoliosis (CS) and adolescent idiopathic scoliosis (AIS) in zebrafish models. However, only one human variant of PTK7 has been reported previously in a patient with AIS. In this study, we systemically investigated the variant landscape of PTK7 in 583 patients with CS and 302 patients with AIS from the Deciphering Disorders Involving Scoliosis and COmorbidities (DISCO) study. We identified a total of four rare variants in CS and four variants in AIS, including one protein truncating variant (c.464_465delAC) in a patient with CS. We then explored the effects of these variants on protein expression and sub-cellular location. We confirmed that the c.464_465delAC variant causes loss-of-function (LoF) of PTK7. In addition, the c.353C>T and c.2290G>A variants identified in two patients with AIS led to reduced protein expression of PTK7 as compared to that of the wild type. In conclusion, LoF and hypomorphic variants are associated with CS and AIS, respectively.

Highlights

Protein tyrosine kinase (PTK7), known as colon carcinomakinase-4 (CCK-4), is an evolutionarily conserved atypical receptor tyrosine kinase
A total of 885 Han Chinese individuals who received a diagnosis of congenital scoliosis (CS, n = 583) and adolescent idiopathic scoliosis (AIS, n = 302) were recruited between 2009 and 2018 at Peking Union Medical College Hospital (PUMCH) for the Deciphering disorders Involving Scoliosis and COmorbidities (DISCO, http://discostudy.org/, accessed on 1 November 2021) project
The criteria for the diagnosis of congenital scoliosis and adolescent idiopathic scoliosis were as follow: congenital scoliosis was caused by vertebral defects, and may be associated with rib anomalies, while idiopathic scoliosis was diagnosed by spinal curvature exceeding 10◦ on a plain antero-posterior X-ray image, with no other identifiable underlying disease

Summary

Introduction

Protein tyrosine kinase (PTK7), known as colon carcinomakinase-4 (CCK-4), is an evolutionarily conserved atypical receptor tyrosine kinase. PTK7 plays an important role in vertebrate canonical and non-canonical Wnt (planar cell polarity, PCP), Semaphorin/Plexin and vascular endothelial growth factor (VEGF) signaling pathways [2,3,4,5]. These signaling pathways are important for embryonic developmental processes, including tissue specification, axial morphogenesis, formation of the cardiovascular, endocrine and immune systems, and regulation of neural crest migration and tumorigenesis [6,7,8,9,10]. Zebrafish models depleted of ptk presented various spinal curve phenotypes. The association between human PTK7 variants and scoliotic phenotypes continue to be understudied

Methods

Results

Discussion

Conclusion