JPM | Free Full-Text | Elucidating the Impact of Deleterious Mutations on IGHG1 and Their Association with Huntington’s Disease

Huntington’s disease (HD) presents an enduring challenge within the landscape of neurodegenerative disorders [1]. It is a hereditary disorder characterized by a relentless progression of motor dysfunction, cognitive deterioration, and psychiatric disturbances [2]. With an incidence of approximately 5 to 10 cases per 100,000 individuals worldwide, HD represents one of the most prevalent autosomal dominant inherited neurodegenerative conditions [3]. The disease compromises language abilities, and there is evidence that the pragmatic aspects of communication are impaired in the early stages of the disease [4]. The disease progression follows a characteristic pattern of brain atrophy, beginning in the basal ganglia structures [4]. HD is devastating to patients and their families, with autosomal dominant inheritance, onset (typically) in the prime of adult life, a progressive course, and a combination of motor, cognitive, and behavioral features [5]. Motor dysfunction normally manifests as involuntary choreiform movements, which may progress to dystonia, bradykinesia, and akinetic-rigid symptoms in the advanced stages of the disease [6]. Cognitive decline in HD encompasses deficits in executive function, attention, visuospatial processing, and working memory, culminating in profound dementia as the disease advances [7]. Additionally, behavioral features, such as depression, anxiety, irritability, and apathy, are prevalent throughout the disease [8].

Overall, HD remains a challenging condition with limited therapeutic options [9]. At the neuropathological level, HD is characterized by the selective degeneration of neurons within the striatum, particularly the medium spiny neurons of the caudate nucleus and putamen [10]. This neurodegeneration is accompanied by widespread atrophy of the cerebral cortex, thalamus, and other subcortical structures, leading to global alterations in brain structure and function. The underlying molecular mechanisms driving neuronal dysfunction and death in HD involve a complex interplay of genetic, epigenetic, and environmental factors [11]. An expansion of CAG trinucleotide causes HD repeats within the huntingtin gene located on chromosome 4p16.3, leading to an elongated polyglutamine tract in the huntingtin protein [12]. The length of the CAG repeat tract inversely correlates with the age of disease onset, with longer repeats typically associated with earlier onset and more severe clinical phenotypes. While the expanded CAG repeat is the primary genetic determinant of HD, numerous modifier genes and environmental factors influence disease penetrance, expressivity, and progression [13].

Despite decades of dedicated research, the precise mechanisms governing HD pathogenesis remain incompletely elucidated [14]. There is an urgent need for disease-modifying therapies that can halt or slow the progression of HD, making elucidating disease mechanisms and identifying therapeutic targets a top priority in HD research. In recent years, advances in genomic technologies, neuroimaging techniques, and biomarker discovery have provided unprecedented insights into the pathobiology of HD [15]. Genome-wide association studies (GWASs) have identified genetic variants associated with HD onset, progression, and phenotypic variability [16,17]. Cerebrospinal fluid (CSF) has emerged as a promising arena for biomarker discovery that offers glimpses into the molecular complexities of various neurodegenerative diseases, including HD [18]. CSF serves as a reservoir of proteins, metabolites, and other molecules that mirror the pathophysiological alterations occurring within the central nervous system (CNS) [19]. Among the CSF proteins, immunoglobulin heavy constant gamma 1 (IGHG1) has been implicated in the disease process due to its elevated levels in HD [20,21,22].

Recent studies have shifted towards the genetic foundations of HD that explore the potential influence of deleterious mutations in driving disease pathogenesis [23,24]. The IGHG1 gene that encodes the gamma-1 chain of the immunoglobulin G (IgG) has emerged as a potential target, with emerging evidence suggesting its involvement in HD etiology [21,22]. Understanding the effects of amino acid substitutions within a protein is vital for elucidating their contributions to disease pathogenesis and identifying potential therapeutic targets [25,26,27].

Our approach encompasses a multifaceted analysis that integrates predictions from multiple computational platforms such as SIFT [28], PolyPhen-2 [29], FATHMM [30], SNPs&Go [31], mCSM [32], DynaMut2 [33], MAESTROweb [34], PremPS [35], MutPred2 [36], and PhD-SNP [37]. By studying the impact of these variants on protein structure, stability, and function, we seek to delineate their potential role in the disrupting IGHG1-mediated processes implicated in HD pathogenesis. We focus on variants localized within specific domains of the IGHG1 protein, particularly the Ig-like 1 domain, which plays a crucial role in protein-protein interactions and immune function. By pinpointing mutations with a propensity to impair protein solubility and disrupt essential protein dynamics, we aim to elucidate their contribution to HD pathology. Ultimately, our findings promise to uncover novel insights into the molecular mechanisms driving HD. By elucidating the role of deleterious variants in IGHG1 and their association with HD, we aim to lay the foundation for developing targeted therapies and precision medicine approaches to mitigate the devastating impact of this debilitating disorder.

HD remains a persistent challenge within the landscape of neurodegenerative disorders [48]. The molecular complexity of HD is substantial, and despite significant progress in understanding its molecular and cellular mechanisms, effective therapeutics are not yet available [49]. Studies have suggested that CSF could be a valuable source of biomarkers for HD [18,21]. IGHG1 is one of the proteins found in CSF and has been found to increase significantly in HD [22]. Considering its critical role in HD, it is reasonable to study the potential involvement of deleterious mutations in IGHG1 in the pathogenesis of this disorder. This study explored the complex landscape of deleterious mutations within the IGHG1 protein and their possible implications in HD pathogenesis.

At the same time, the structure-based predictions enhanced our confidence in identifying mutations that potentially play important roles in disease manifestation and progression. This observation underscores the potential implications of these mutations in perturbing protein solubility and highlights their relevance in disease pathogenesis [50]. Furthermore, our analysis revealed the aggregation propensity of IGHG1 variants, shedding light on their potential contribution to disease progression [51].

Developing non-dissolvable protein aggregates is a hallmark of HD [52]. Here, two substitutions (Y32C and P34S) were identified that decrease protein solubility, suggesting their potential role in protein IGHG1 and subsequent disease manifestation. Additionally, analyzing residual frustration in a protein structure is crucial in shedding light on the disease mechanism [53]. The frustration analysis provided valuable insights into the complex energy landscapes of IGHG1, highlighting regions of potential instability that could influence protein function and contribute to disease pathology. The analysis showed that mutations occurring in the minimally frustrated residues of IGHG1 could disrupt stability, thereby affecting the function of the protein and potentially contributing to HD pathogenesis. This analysis underscores the importance of considering local frustration in elucidating the molecular mechanisms underlying disease pathology.