Genetic Variant of ROBO3 Gene Is Associated with Adolescent Idiopathic Scoliosis in the Chinese Population

Abstract

Study Design. A case-control association study. Objectives. This study aimed to reveal whether mutations within roundabout receptor 3 (ROBO3) gene were related to adolescent idiopathic scoliosis (AIS) in Chinese Han population and to investigate the functional role of ROBO3 in the pathogenesis and progression of AIS. Summary of Background Data. ROBO3 is essential for the regulation of hindbrain axonal cell migration and midline crossing. Studies have demonstrated that ROBO3 homozygous mutations are associated with horizontal gaze palsy with progressive scoliosis. However, whether and how ROBO3 contributed to the development of scoliosis remains unclear. Materials and Methods. Whole exome sequencing was performed in 135 AIS patients and 267 healthy controls to evaluate the differences of single nucleotide polymorphism variants within ROBO3. Then the identified variant of ROBO3 was genotyped in another cohort included 1140 AIS patients and 1580 controls. Moreover, paraspinal muscles were collected from 39 AIS patients and 45 lumbar disk herniation patients for the measurement of ROBO3 mRNA expression. The χ2 test, Fisher exact test or the Student t test were used to compare intergroup data. Pearson correlation was used to determine the association between ROBO3 expression and clinical phenotypes. Results. A significant association was identified between the gene variant (rs74787566) of ROBO3 and the development of AIS through exome sequencing. The genotyping cohort demonstrated a higher frequency of allele A in AIS patients compared to controls (7.89% vs. 4.30%, P<0.001, odds ratio=1.87). In addition, the expression of ROBO3 in paraspinal muscles was inversely correlated with the Cobb angle (P=0.043, r 2=0.1059). Conclusion. A significant association was identified between the gene variant (rs74787566) of ROBO3 and the development of AIS. The reduced expression of ROBO3 could result in the progression of curve magnitude in patients with AIS. Further studies are needed to verify the functional role of ROBO3 in the development of AIS. Level of Evidence. Level III.

Idiopathic scoliosis in subjects with eye diseases: A systematic review with meta‐analysis

“…42 More recently, a significant association has been found between the gene variant (rs74787566) of ROBO3 and the development of adolescent idiopathic scoliosis (AIS). 43 The fact that some ROBO3 gene polymorphisms have been related to lateral gaze disorders is compatible with our finding of a higher prevalence of IS in subjects with strabismus, especially concomitant exotropia. 38,40 However, in our work, the range of vision disorders associated with IS was diverse, ranging from severe visual impairment 44 to the presence of myopia 37,39 and anisometropia 41 (the difference in refractive error between both eyes).…”

“…The relationship between vision impairment and the presence of IS has previously been analyzed, specifically the association of ROBO3 gene polymorphisms and horizontal gaze palsy 42 . More recently, a significant association has been found between the gene variant (rs74787566) of ROBO3 and the development of adolescent idiopathic scoliosis (AIS) 43 . The fact that some ROBO3 gene polymorphisms have been related to lateral gaze disorders is compatible with our finding of a higher prevalence of IS in subjects with strabismus, especially concomitant exotropia 38,40 …”

Novel variants and phenotypes of ROBO3 gene associated with horizontal gaze palsy with progressive scoliosis

“…This may be due to chronic muscle tone abnormalities caused by brainstem malformation involving posterior column structures and associative descending fibers from the brain to the spinal cord, including the reticulospinal and corticospinal tracts. 9,10 With exceptions of loss of conjugate horizontal movement and scoliosis, our patient presents a series of atypical phenotypes, such as vertical nystagmus, poor convergence, asynchronous blink, paroxysmal head jerk or nodding, inflexible tongue movements, difficulty swallowing, gait instability, and motor development delay, among which the phenotypes of abnormal horizontal tongue movement and brachycephaly have not been reported in HGPPS patients previously. Because of logistical reasons, we were unable to perform skull radiographs to further confirm the suspected craniosynostosis, which may be considered as an additional unreported deformity.…”

“…This may be due to chronic muscle tone abnormalities caused by brainstem malformation involving posterior column structures and associative descending fibers from the brain to the spinal cord, including the reticulospinal and corticospinal tracts. 9 , 10 …”

Advances in genetic factors of adolescent idiopathic scoliosis: a bibliometric analysis

“…High expression of the TENT5A gene facilitates myofiber maturation by promoting the proliferative migration of myofibroblasts and maintaining the stability of myogenin; whereas, the TENT5A gene is lowly expressed in the paraspinal muscles of patients with AIS ( 54 ). In addition to the genes mentioned above, numerous other genes are lowly expressed in the paraspinal muscles of AIS patients, and their functions have yet to be investigated, including PIEZO2 ( 55 ), CDH13 ( 56 ), ABO ( 57 ), SLC39A8 ( 58 ), ROBO3 ( 59 ), IRX1 ( 60 ), H19 ( 61 ) and SOCS3 ( 62 ).…”