It is noteworthy that out of the 35 patients with scoliosis 68.5% had normal genes and only 31.5% had gene mutations, and that AVR was more severe in mutant cohorts than that in no-mutant cohorts both in DLS patients and their offspring. Additionally, more scoliosis was detected in offspring cohorts with susceptibility genes, they all presented the same scoliosis orientation and apex vertebrae/disc location with their parents. Our research delved into the possibility of a genetic predisposition to the specific scoliosis phenotype, which could be attributed to the inheritance of pathogenic genes. We hypothesized that these genes might influence skeletal development and spinal alignment through pathways that are not yet fully understood. To explore this hypothesis, we conducted a comprehensive analysis of the genomic data from our patient cohorts and denote that variants such as COL12A1, FLNA, FLNB, FN1, MAPK7, RYR1, POC5, FBN1, and FBN2 may exhibit associations with DLS phenotypes. It is imperative to underscore that the presence of DLS-associated variants does not establish causality but rather signifies potential candidate genes in linkage disequilibrium with the disease. Intriguingly, these genes were found to be involved in the regulation of bone morphogenesis, extracellular matrix organization, and signaling pathways that have been implicated in vertebral development. This suggests that mutations in these genes could disrupt normal spinal development processes, leading to the manifestation of a similar scoliosis phenotype in affected family members.
Collagen Type XII, encoded by the COL12A1 gene, is integral to the extracellular matrix’s architecture through its interaction with other matrix macromolecules [9]. This interaction is critical for preserving the structural integrity of connective tissue. Pathogenic variants in COL12A1 can perturb these molecular interactions, leading to compromised assembly of the fibronectin-collagen matrix, which is indispensable for the biomechanical resilience and pliability of spinal tissue [10]. Such disturbances may induce alterations in the biomechanical properties of the vertebral column. Cells harboring these mutations demonstrate aberrant mechanotransduction signaling, a process essential for cellular adaptation to mechanical stimuli [11]. This dysregulated signaling is implicated in the etiology of abnormal spinal curvature due to the inability to adequately redistribute mechanical forces, potentially exacerbating the progression of scoliosis. Given these insights, we advocate for the incorporation of COL12A1 mutation screening in clinical settings to preemptively identify individuals predisposed to DLS. Additionally, the development of pharmacotherapies aimed at the molecular derangements observed in patients with COL12A1 mutations holds promise. Therapeutic agents that fortify the extracellular matrix or modulate mechanotransduction pathways may offer clinical benefits.
The FLNA and FLNB loci are responsible for the synthesis of filamin A and B, which are integral cytoplasmic actin-binding proteins that are pivotal in sustaining cellular architecture and modulating intracellular signaling cascades [12]. These proteins influence the architectural integrity of the cytoskeleton, cellular adherence, and the modulation of signaling networks. Mutations within these genes may perturb these critical processes, potentially altering the biomechanical attributes of the soft connective tissue within the lumbar spine, thereby contributing to the pathogenesis of scoliotic deviations [13]. Specifically, the resultant aberrant protein may impair the biomechanical functionality of the intervertebral discs and ligaments, heightening their vulnerability to degeneration when subjected to normal physiological loads. The ensuing degradation of these connective structures can lead to disproportionate mechanical stress on the vertebral column, which could amplify spinal curvature, culminating in scoliosis. The incorporation of genetic assays for FLNA and FLNB mutations into the diagnostic algorithm for scoliosis could enable precocious clinical interventions, potentially decelerating the disease’s progression. Moreover, longitudinal investigations tracking individuals harboring FLNA and FLNB mutations could illuminate the etiopathogenic trajectory of DLS and pinpoint opportune junctures for clinical intervention.
The FN1 locus, responsible for the synthesis of fibronectin, is integral to cellular adhesion, proliferation, motility, and tissue repair processes [14]. Genetic aberrations within this locus may disrupt the mechanical attributes of the lumbar spine’s extracellular matrix, culminating in asymmetric mechanical stress distribution and ensuing spinal malformation. Prior investigations have established the prevalence of fibronectin within the nucleus pulposus of intervertebral discs, underscoring its necessity for disc integrity [15]. An allelic variation in FN1 may undermine the structural and functional coherence of the intervertebral disc, potentially instigating or aggravating degenerative disc disease.
The allelic variation within the MAPK7 gene, which influences the enzymatic activity of mitogen-activated protein kinase 7, plays a crucial role in the MAPK signal transduction cascade [16]. This cascade is involved in an array of cellular mechanisms such as cell growth, morphological differentiation, and programmed cell death. Mutations in the MAPK7 locus may perturb these integral vertebral processes, potentially precipitating anomalous spinal curvature formation [17]. Theoretically, a polymorphism in MAPK7 could compromise the viability and function of bone-forming osteoblasts or bone-resorbing osteoclasts, thereby altering skeletal homeostasis and possibly exacerbating the development of scoliosis.
The RYR1 locus is responsible for coding the ryanodine receptor, an integral transmembrane channel facilitating the efflux of calcium ions from the sarcoplasmic reticulum within myocytes [18]. Pathogenic variants in this locus can lead to dysregulation of calcium ionostasis, potentially impairing myofibrillar contraction dynamics and sequentially influencing axial skeleton biomechanics [19]. Electrodiagnostic studies, in the form of electromyography, alongside histopathological examination of muscular tissue, can elucidate the pathophysiological impact of RYR1 aberrations on musculoskeletal function and their role in the pathogenesis of progressive lumbar spinal deformities.
The POC5 gene, known for its involvement in centriole formation, may influence the integrity of the cytoskeletal structure within spinal cells, thereby affecting their ability to maintain proper alignment and resist degenerative forces [20]. Recent studies have suggested that the aberrant expression of POC5 can lead to altered microtubule dynamics, which, in turn, could compromise the structural stability of intervertebral cells [21]. This instability may predispose the spinal column to abnormal curvature, particularly under the continuous mechanical stress experienced by the lumbar region. Furthermore, the presence of the POC5 variant has been correlated with an accelerated degeneration of disc tissue, exacerbating the propensity for scoliosis development.
The FBN1 gene encodes fibrillin-1, a glycoprotein that is essential for the formation of elastic fibers within connective tissue [22]. Mutations in this gene have been associated with Marfan syndrome, which features a range of skeletal abnormalities. The FBN2 gene, on the other hand, encodes fibrillin-2, playing a similar, yet distinct role in the microfibrillar network, primarily during early development [23]. Further exploration of the pathophysiology reveals that aberrations in these genes could disrupt the intricate balance of extracellular matrix production and degradation, leading to compromised structural integrity of the spinal column. This imbalance may result in the vertebrae becoming susceptible to asymmetric loading and the subsequent development of scoliosis.
In conclusion, our findings emphasize the significance of genetic factors in the development and progression of scoliosis. The identification of susceptibility genes and their associated pathways offers valuable insights into the etiology of this condition and presents new opportunities for early diagnosis and intervention. Future research should focus on the functional characterization of these genes to unravel the precise mechanisms by which they contribute to scoliosis pathogenesis. This could lead to the development of novel therapeutic approaches that target the molecular basis of the disease, offering hope for improved patient outcomes. There were several potential limitations in this study. First, only Chinese Han individuals were included in the current study and Ethnic variation was not covered. Second, the number of patients included was relatively small, and the study may be under powered to detect the potential susceptibility genes that may influenced the DLS, further validation of large sample clinical data from multiple centers is needed in the future.
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