Proprioception‐related gene mutations in relation to the aetiopathogenesis of idiopathic scoliosis: A scoping review

Since idiopathic scoliosis is a multifactorial disorder, the proprioceptive defect is considered one of its etiological factors. Genetic studies have separately revealed this relationship, yet it remains indeterminate which specific genes that related to proprioception contributed to the initiation, progression, pathology, and treatment outcomes of the curvature. A systematic search was conducted on four online databases, including PubMed, Web of Science, Embase, and Academic search complete. Studies were included if they involved human or animal subjects with idiopathic scoliosis and evaluated with proprioceptive genes. The search period was the inception of the database to February 21, 2023. Four genes (i.e., Ladybird homeobox 1 [LBX1], Piezo type mechanosensitive ion channel component 2 [PIEZO2], Runx family transcription factor 3 [RUNX3], and neurotrophin 3 [NTF3]) investigated in 19 studies were included. LBX1 has confirmed the correlation with the development of idiopathic scoliosis in 10 ethnicities, whereas PIEZO2 has shown a connection with clinical proprioceptive tests in subjects with idiopathic scoliosis. However, curve severity was less likely to be related to the proprioceptive genes. The potential pathology took place at the proprioceptive neurons. Evidence of proprioception‐related gene mutations in association with idiopathic scoliosis was established. Nevertheless, the causation between the initiation, progression, and treatment outcomes with proprioceptive defect requires further investigation.

However, curve severity was less likely to be related to the proprioceptive genes.
The potential pathology took place at the proprioceptive neurons.Evidence of proprioception-related gene mutations in association with idiopathic scoliosis was established.Nevertheless, the causation between the initiation, progression, and treatment outcomes with proprioceptive defect requires further investigation.

| INTRODUCTION
Idiopathic scoliosis affects approximately 4% of the population, 1,2 thus making it the commonest form of spinal deformity.Its most recognizable feature is the lateral curvature of the spinal column. 3me scoliotic individuals would require active intervention like bracing or surgery when the curve is likely progressive or severe. 4,5vertheless, the etiology of idiopathic scoliosis remains elusive even following decades of research.Since various susceptibility loci have been identified by genome-wide linkage analyses, 6 current evidence has suggested idiopathic scoliosis as a multifactorial disorder. 7While genetic basis undoubtedly contributes to the development of idiopathic scoliosis, its interplay on the initiation and progression of the curve is still not known.
Proprioceptive defect, is proposed to be associated with idiopathic scoliosis in recent literature. 8In general, proprioception is the ability to sense body and limb position. 9This sensation is mainly innervated by two mechanoreceptors (i.e., muscle spindles and Golgi tendon organs), which react with the change in the length of muscles and the muscle tone. 10These organs autonomously generate responses in afferent nerve fibers (i.e., proprioceptive neurons), thereby transmitting the signal via the dorsal root ganglia to the spinal cord, and eventually modulating local muscles in the formation of the reflex arches. 11Despite peripheral proprioception has been proven to be impaired in subjects with idiopathic scoliosis, 8 the causal relationship in between is still largely unknown.
Interestingly, a mice model with a deficient transcription factor induced human-like scoliosis. 12This genetic expression triggered muscle spindle agenesis, apoptosis of proprioceptive neurons, and obstruction of sensory afferents. 12In consequence, the model was found to have proprioceptive dysfunction.Meanwhile, clinical assessment of spinal proprioception has been explicitly developed for scoliotic adolescents recently. 13It would tie in with the genetic findings and support proprioception as an etiological factor when the spinal proprioceptive defect is demonstrated.Nonetheless, little is known about how proprioception of the spine alters the prognosis of idiopathic scoliosis.
Given the hints of the association between idiopathic scoliosis and proprioception, the genetic clue should be further addressed to ascertain this relationship.Therefore, this review aimed to identify the specific proprioception-related genes tested in subjects with idiopathic scoliosis.It also aimed to evaluate the effects of proprioceptive genes on the development of idiopathic scoliosis.With this information, future studies may replicate the included genes and establish their relationship with idiopathic scoliosis.
Further investigation may also examine thoroughly how proprioception is featured in clinical outcomes to help clinicians better understand and manage this spinal condition.

| Eligibility criteria
To fulfill the study objective, primary studies were included if they had subjects with scoliosis and investigated genes that related to proprioception.Both human and animal studies were also included.
The exclusion criteria were shown as follows, (1) subjects with a diagnosis of congenital, neuromuscular, or syndromic scoliosis, (2) the tested gene was not directly relevant to proprioception, (3) the outcome measure was not evaluating gene mutation, (4) review, (5) commentary, (6) conference proceeding, and (7) preprint.No limitation was restricted by the study design, language of the article, or date of publication.

| Information sources
Searches were implemented systematically on four online databases, comprising PubMed, Web of Science core collection, Embase from Ovid, and Academic search complete from EBSCOhost.The availability of databases was subject to the provision of the affiliated university library.The initial search was done on October 31, 2022, whereas the most recent search was executed on February 21, 2023.Furthermore, references from the included papers and the forward citation search via Scopus were performed for additional studies that met the predefined criteria.

| Search strategy
The following terms were used throughout all databases, [scoliosis] AND [proprioception OR position sense OR postural balance OR postural control OR somatosensory] AND [gene].These phrases were picked according to the medical subject headings produced by the National Library of Medicine, and they are designed for searching biomedical and health-related information.Searching of keywords in the full-text was adopted, and no limits were set during the search.

| Study selection
Traditional three stages of citation screening were implemented by two independent reviewers.Initially, duplicates were removed manually and confirmed by the automation tool in the reference management software (i.e., EndNote).The title-abstract screen was then performed, and the papers that were uncertain of appropriateness were carried over to the next stage.Lastly, the full-text screen was conducted to affirm the eligibility.Each reviewer underwent all screening stages.Evaluation of screening results was organized in every stage and discrepancies were settled by discussion.Moreover, references from the included papers were screened by the title, and the inclusion of studies was determined by a full-text screen.The forward citation search followed the same procedure as in the literature screening.

| Data charting
A standardized form with all data items was utilized to collect data from the included studies.Information regarding the included studies was summarized in terms of general information (i.e., the country took place, study design, and type of subject), demographics (i.e., sample size, age, and gender), scoliosis-specific data (i.e., Cobb angle of the major curve and treatment received), and candidate genes tested with specific variants.An experienced researcher did the extraction of data, which was further checked by another investigator.

| Selection of sources of evidence
The systematic search of the literature retrieved 159 citations, and 60 duplicates were removed before the screening.The remaining 98 records then underwent the title abstract screen.After 85 records were excluded, 13 reports sought retrieval and were assessed for eligibility.Of them, reports were excluded because subjects were not diagnosed with idiopathic scoliosis (n = 7) and the outcome measure was irrelevant to proprioception (n = 1).From the five temporary included papers, three extra reports were retrieved from their reference lists.Further, the forward citation search located 11 more relevant reports.5][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] The flow diagram of the study selection is illustrated in  (n = 3), respectively.Apart from the human subjects, mice and zebrafish were employed as study subjects.While the age spread was diverse among the included studies, females accounted for a higher proportion.As for the condition of idiopathic scoliosis within the study group, four of them had a mixed curve severity group, three had a surgery-only group, one had an observation-only group, and eight studies did not report any information about the curves.With regard to genetics, four proprioception-related genes were identified.
The information of each study is presented in Table 1.

| Ladybird homeobox 1 (LBX1)
Fifteen studies have evaluated the association between the mutation of LBX1 and the development of idiopathic scoliosis.This is the only gene confirmed by large-scale studies with replication in other races.

| Piezo-type mechanosensitive ion channel component 2 (PIEZO2)
Two studies examined whether PIEZO2 deficiency was found in subjects with idiopathic scoliosis.Nonetheless, this gene was the only one verified with clinical proprioceptive outcomes.Wu et al. 30 assessed proprioception through the Unterberger stepping test in subjects with adolescent idiopathic scoliosis.Another team has tried to discover the potential pathology of scoliosis with PIEZO2 mutation.

| Individual outcomes
An animal study on the Runx family transcription factor 3 (RUNX3) knockout mice found an elevated incidence of prepubertal scoliosis than the control group.Pathologically, they have shown that neuronal loss of RUNX3 caused scoliosis without affecting spinal tendons or intervertebral discs, whereas loss of muscle spindles caused a less severe curvature. 23A case-control study explored the potential relation of neurotrophin 3 (NTF3) in the susceptibility, curve severity, and bracing effectiveness of idiopathic scoliosis.Although they have not found any correlation with the occurrence, smaller Cobb angles and higher success rates of bracing in those with defective NTF3 than their counterparts were demonstrated. 14

| DISCUSSION
This review identified three genes related to proprioception significantly associated with the development of idiopathic scoliosis, including LBX1, PIEZO2, and RUNX3.Besides, some included studies have also shown that mutated proprioceptive genes may be correlated with curve severity and treatment success, as well as its potential role in the pathology of idiopathic scoliosis.
Of the proprioceptive genes, LBX1 was strongly implicated as an etiological factor for idiopathic scoliosis.This gene is expressed in the dorsal part of the spinal cord and hindbrain and muscle precursor cells. 33One of its functions is known to be a selector gene in determining the fates of dorsal spinal and hindbrain somatosensory neurons. 34,35It can also modulate the migration of muscle precursor cells during embryonic development and on myoblast differentiation. 36Guo et al. 22 demonstrated that overexpression of LBX1 could lead to the onset of scoliosis (i.e., an observed body axis curvature) in zebrafish embryos.Results from Jennings et al. 27 and Xu et al. 31 have implied that paraspinal muscles were likely to be affected by the LBX1.To date, LBX1 mutation was simultaneously found in scoliotic subjects of various ethnicities, including Japanese, Hongkongers, Chinese, Americans, Swedes, Danes, Canadians, French, Bulgarians, and Poles.With reference to the distinctive prevalence of idiopathic scoliosis in different countries, 37 it could substantiate that LBX1 uniquely contributed to the incidence of idiopathic scoliosis without being affected by the genetic variation among races.
As for the PIEZO2, it is a stretch-activated ion channel expressed in somatosensory neurons, 38 which convey information about tension and stretch experienced by joints, skin, muscles and tendons. 39It is believed that PIEZO2 is responsible for the transduction of rapidly adapting mechanically activated currents in the neurons of the dorsal root ganglia. 40People with PIEZO2 mutation have variants that render both alleles nonfunctional, either through premature stop codons that result in channels with no pore domain or damaging missense mutations in the critical structural domains. 41Interestingly, results from the mice model implied that only proprioceptive loss of PIEZO2 could affect the spine but not skeletal cells. 29Vertebrae and surrounding tissues were largely unaffected by the PIEZO2 loss as well. 29Furthermore, Wu et al. 30 found that when divided subjects into impaired and unimpaired proprioception groups, the expression of PIEZO2 and the average number of muscle fibers in the muscle spindle of paraspinal muscles were significantly decreased in those impaired.
It has been shown that PIEZO2 is directly related to proprioception, yet this mutant seems to happen only in a subgroup of scoliotic subjects.
On the other hand, RUNX3 is a member of a family of transcription factors that are important to activate or suppress gene expression. 42It is also essential for the maintenance of cell identity of proprioceptive dorsal root ganglion neurons and responsible for controlling the connection between the sensory neurons and motor neurons. 43While Blecher et al. 23  There are some limitations noted in the present review.The systematic review and/or meta-analysis was not embraced in the current topic because of the scarcity of studies with a high level of evidence.Although results could not be summarized, this review has established the gene mutation of proprioception in idiopathic scoliosis.In addition, the strength of the evidence was greatly reduced by the quality of the included papers.Detailed demographics of participants and the status of scoliosis were missing in some studies, for instance, age and curve magnitude.

| CONCLUSION
This scoping review identified three significant proprioceptionrelated gene mutations associated with the development of idiopathic scoliosis.While LBX1 affirmed its association but not with clinical proprioception outcomes, PIEZO2 requires further justification for its predisposition with the scoliotic population.However, curve progression and treatment outcomes with defective genes of proprioception were still ambiguous.Future investigation should focus on the clinical perspective and presentation of proprioceptive performance in subjects with idiopathic scoliosis.
the inception of the database to February 21, 2023.Four genes (i.e., Ladybird homeobox 1 [LBX1], Piezo type mechanosensitive ion channel component 2 [PIEZO2], Runx family transcription factor 3 [RUNX3], and neurotrophin 3 [NTF3]) investigated in 19 studies were included.LBX1 has confirmed the correlation with the development of idiopathic scoliosis in 10 ethnicities, whereas PIEZO2 has shown a connection with clinical proprioceptive tests in subjects with idiopathic scoliosis.
Outcome synthesisStudies were grouped by the genes scrutinized commonly.Outcome measures related to the association between idiopathic scoliosis and proprioception, as well as the effects of proprioception on the pathology, prognosis, and treatment success of the curvature, were reported descriptively.

3. 2 |
Characteristics of sources of evidence The included studies were published between 2011 and 2022 from 11 countries which consisted of Bulgaria, Canada, China, Denmark, France, Hong Kong, Israel, Japan, Poland, Sweden, and the United States.Sample size varied among studies ranging from 59 to 12,763 and 12 to 105 for case-control studies (n = 15) and animal studies F I G U R E 1 Flow diagram of study selection.
Characteristics of the included studies.-scale studies with various races.More importantly, impaired balance performance, abnormal gait, and poor proprioception are presented in scoliotic subjects.It is hypothesized that proprioceptive defect as an etiological factor account for a considerable subgroup of idiopathic scoliosis.Alternately, a multivariate analysis of all genes confirmed the association with developing scoliosis, including LBX1 should be elucidated.Given that the proprioceptive gene is proven to be related to the clinical presentation of proprioception in scoliotic subjects, it remains unclear whether alteration in proprioception, like physiotherapy, would induce changes in curvature and treatment effect.
have revealed its relationship with idiopathic scoliosis, no human clinical trial has been done with T A B L E 1