Research Progress on the Pathogenesis and Diagnostic and Therapeutic Potential of Ciliopathies Regulated by IFT172

ABSTRACT

IFT172 is a core component of intraflagellar transport complex B (IFT‐B), and pathogenic IFT172 variants disrupt ciliary transport, receptor localization, and tissue‐specific signaling. This review summarizes evidence linking IFT172 dysfunction to neurological, retinal, skeletal, renal, and syndromic ciliopathy phenotypes, with emphasis on Bardet‐Biedl syndrome, Joubert‐spectrum disease, orofaciodigital syndrome, Mainzer–Saldino syndrome, and retinal degeneration. Current data support a primary role for IFT172 in IFT‐train assembly, tip remodeling, anterograde‐to‐retrograde transition, and cilia‐dependent signaling; downstream metabolic, oxidative, and inflammatory changes are interpreted as context‐dependent secondary modules rather than uniform linear cascades. We further discuss diagnostic interpretation and the practical boundaries of gene, splice‐correction, and pathway‐modulation strategies. By aligning molecular mechanisms with organ vulnerability, this review provides a concise framework for interpreting IFT172‐associated ciliopathies and for prioritizing future translational studies.

IFT172‐associated ciliary trafficking and its regulatory mechanisms on Wnt and Hedgehog signaling pathways. This schematic illustrates how defects in IFT172‐mediated primary cilia transport disrupt core developmental and homeostatic signaling pathways: Wnt Signaling: IFT172 dysfunction impairs the localization of receptors and downstream components (e.g., Dishevelled) at the ciliary/periciliary region, leading to aberrant stabilization, nuclear translocation of β‐catenin, and imbalanced TCF/LEF‐dependent transcription. This is linked to neurodevelopmental disorders like Joubert syndrome and skeletal polarity defects. Hedgehog Signaling: IFT172 is critical for IFT particle assembly and receptor trafficking. Its mutation hinders ciliary enrichment and activation of SMO, disrupting the balance between activator (GliA) and repressor (GliR) forms of Gli transcription factors, which results in aberrant expression of Hedgehog target genes. This represents a core mechanism underlying skeletal malformations (e.g., short‐rib thoracic dysplasia) and Orofaciodigital syndrome (OFD).

Abbreviations

BBS

Bardet‐Biedl Syndrome

EVC

Ellis‐Van Creveld Syndrome

GPCR

G Protein‐Coupled Receptor

IFT

Intraflagellar Transport

IFT‐A

Intraflagellar Transport Complex A

IFT‐B

Intraflagellar Transport Complex B

JS

Joubert Syndrome

JSRDs

Joubert Syndrome‐Related Disorders

MSS

Mainzer‐Saldino Syndrome

NPHP

Nephronophthisis

OFD

Orofaciodigital Syndrome

SRPS

Short Rib‐Polydactyly Syndrome

SRTD

Short Rib Thoracic Dysplasia

WES

Whole‐Exome Sequencing

1. Introduction

Primary cilia are microtubule‐based signaling organelles that concentrate receptors, ion channels, and downstream effectors required for development and tissue homeostasis [1, 2, 3]. Disruption of ciliary structure or signaling causes ciliopathies that frequently involve the retina, nervous system, skeleton, and kidney [4, 5]. Photoreceptors are especially sensitive because outer‐segment renewal and phototransduction depend on continuous ciliary trafficking [6].

Ciliary growth and maintenance rely on intraflagellar transport (IFT), in which IFT‐B mediates anterograde movement toward the tip and IFT‐A supports retrograde return to the base [7] IFT172 is the largest IFT‐B protein and has been described as a scaffold‐like organizer that links microtubule‐associated transport, IFT‐particle assembly, and ciliary cargo delivery [8, 9]. Cross‐species studies support its importance for ciliogenesis and Hedgehog‐related developmental signaling. Pathogenic IFT172 variants are associated with isolated retinal degeneration and multisystem syndromes including Bardet‐Biedl syndrome (BBS), Joubert syndrome (JS), and Mainzer‐Saldino syndrome [10, 11].

Recent clinical sequencing and rare‐disease registry studies indicate that IFT172 variants occur across diverse populations and include missense, splice‐site, frameshift, and nonsense variants [12, 13, 14, 15]. The same gene can produce distinct organ combinations, suggesting that variant class, domain disruption, tissue‐specific ciliary thresholds, and modifier genes jointly shape disease expression [16]. This review therefore focuses on a streamlined question: how does IFT172 dysfunction connect primary transport defects with organ‐specific phenotypes, and which mechanisms are sufficiently supported to inform diagnostic and therapeutic thinking?

This synthesis prioritizes evidence that clarifies IFT172 structure–function relationships, genotype–phenotype interpretation, and organ‐specific vulnerability. Studies are emphasized when they define a mechanistic node, identify a disease‐relevant domain, or support diagnostic interpretation across neurological, retinal, skeletal, renal, or syndromic phenotypes. This synthesis connects IFT172 dysfunction with ciliary transport failure and tissue‐specific disease through a mechanism‐oriented framework.

An evidence‐graded framework is used to separate primary ciliary events from downstream stress responses. Ciliary shortening, IFT‐particle assembly defects, photoreceptor cargo mislocalization, and altered receptor localization are treated as directly supported mechanisms when documented by genetic, cellular, animal, or clinical studies. Lipid‐metabolic stress, inflammatory signaling, mitochondrial injury, and oxidative amplification are presented as secondary or context‐dependent modules unless their causal sequence has been directly tested in IFT172‐specific models.

Across organ systems, disease severity is best interpreted as the product of allele effect, domain disruption, developmental timing, and tissue‐specific ciliary demand. This framework explains why truncating variants can cause broad syndromic involvement, whereas hypomorphic or domain‐altering variants may present with organ‐biased phenotypes. It also explains why the same transport defect can generate different clinical outputs in photoreceptors, renal tubules, growth‐plate chondrocytes, and neurons.

2. IFT172 Functional Mechanisms and Tissue‐Specific Pathogenesis

2.1. Structural Architecture and IFT‐Train Regulation

IFT172 comprises approximately 1748 amino acids and contains an N‐terminal WD40‐repeat region and a C‐terminal coiled‐coil/clathrin‐homology‐like region [12, 17]. This bipartite organization places IFT172 at the interface of IFT‐B assembly, IFT‐A coupling, Bardet‐Biedl syndrome protein complex (BBSome)‐associated receptor recycling, tip remodeling, and transition‐state organization [18]. Within the IFT‐B complex, IFT172 cooperates with subunits such as IFT57, IFT81, and IFT88 to support core‐particle stability and ciliary entry [19]. Its C‐terminal region can interact with IFT‐A or the BBSome and thereby affect the trafficking or clearance of ciliary membrane receptors [20]. In rod cells, loss of Ift172 causes phototransduction‐protein mislocalization and photoreceptor degeneration, illustrating the functional consequences of impaired ciliary cargo delivery [21]. The organization of IFT172 within bidirectional ciliary transport is summarized in Figure 1.

FIGURE 1.

Structural domains of IFT172 and their links to ciliary transport and organ‐specific phenotypes. Note: Figure 1 illustrates the domain organization of IFT172, its interactions within the IFT transport machinery, and representative tissue‐specific consequences of IFT172 dysfunction. In the schematic, colors are used to distinguish the major components of IFT trains and associated transport modules: IFT‐A (orange), IFT‐B (blue), the BBSome (purple), and transported cargo/membrane proteins (cyan). The anterograde motor kinesin‐2 is indicated by a purple icon, and the retrograde motor dynein by an orange icon. The enlarged panel on the left illustrates the repetitive‐unit assembly of anterograde IFT trains on the surface of axonemal microtubules: IFT‐A and IFT‐B are arranged in a modular manner. IFT172 is positioned on the outer/peripheral (edge) side of the IFT‐B assembly (blue label “IFT172”). Its N‐terminus lies closer to the microtubule track and contributes to particle assembly and maintenance of train stability, whereas its C‐terminus faces toward the IFT‐A side and can form dynamic coupling interfaces with IFT‐A and/or the BBSome, thereby participating in cargo/membrane receptor loading, retrieval, and spatiotemporal regulation of localization. The central overview depicts the bidirectional movement of IFT trains along the ciliary axoneme, including anterograde transport toward the ciliary tip and retrograde transport back to the base. The right panel schematically shows the microtubule‐surface organization of the train during retrograde transport and the corresponding motor‐driven state. Dashed boxes and connecting lines indicate local magnifications and the spatial arrangement of IFT trains on the microtubule surface.

Pathogenic variants provide additional structure–function clues. The p.Leu1564Pro missense variant disrupts the IFT172‐BBSome interface and is associated with multi‐organ ciliopathy [16]. Severe truncating or splice‐disrupting alleles can reduce IFT172 dosage or generate unstable proteins, whereas hypomorphic variants may preserve partial function but weaken assembly, docking, or domain‐specific interactions [22, 23]. In situ cryo‐electron tomography has further shown that IFT trains undergo conformational remodeling at the ciliary tip before retrograde trains form; within this structural framework, IFT172 lies on the peripheral side of the IFT‐B assembly and likely contributes to train stability and transition‐state organization [24, 25].

These findings support a refined interpretation of IFT172 as an active organizer rather than a passive scaffold. Available evidence links IFT172 loss to reduced effective train assembly, altered train frequency, impaired retrograde transition, and delayed kinesin unloading at the tip; however, quantitative effects on train velocity are not yet consistently defined across models. Thus, IFT172‐related transport abnormalities should not be interpreted uniformly as velocity defects.

Compared with IFT89, which mainly stabilizes the IFT‐B core, IFT172 has a larger peripheral architecture and appears more involved in train remodeling and receptor trafficking. Compared with IFT157, an IFT‐A scaffold‐like subunit more closely linked to retrograde organization, IFT172 occupies a coupling position between IFT‐B assembly and IFT‐A/BBSome‐associated cargo return [17, 26]. Therefore, a single IFT172 mutation may affect multiple transport‐ and signaling‐related processes. If the dominant consequence is weakened IFT‐B assembly, cells may show fewer productive trains and reduced cargo entry. If the dominant consequence is impaired IFT‐A or BBSome coupling, ciliary receptors may enter the compartment but fail to recycle correctly. If tip remodeling is affected, anterograde trains may reach the distal cilium but fail to convert efficiently into retrograde trains. These mechanistic alternatives are not mutually exclusive, but separating them improves interpretation of experimental phenotypes and prevents overstatement of a single universal defect.

The same framework clarifies the distinction between train frequency and velocity. Reduced productive train assembly or ciliary entry can lower the number of observable transport events without necessarily slowing the motor‐driven movement of individual trains. Impaired tip conversion can also produce distal accumulation and defective cargo return even when anterograde movement remains detectable. Thus, IFT172 dysfunction is best assessed using separable readouts, including assembly efficiency, train entry, train frequency, tip remodeling, kinesin unloading, retrograde transition, and velocity.

The peripheral position of IFT172 within the IFT‐B assembly supports a model in which structural impairment can affect both cargo loading and train remodeling. Domain‐level lesions may therefore produce different transport readouts: assembly‐related defects are expected to reduce productive anterograde delivery, whereas coupling defects may preferentially disturb transition‐state organization and cargo return. These domain‐dependent effects provide a basis for linking variant classes with distinct mechanistic consequences.

2.2. Variant Classes, Mechanistic Nodes, and Tissue Vulnerability

IFT172 variants can be grouped into two broad functional categories. Near‐null alleles, including nonsense, frameshift, and severe splice variants, tend to decrease IFT172 dosage or produce truncated proteins, resulting in global reduction of IFT‐train assembly and transport capacity [11, 22]. Missense and domain‐altering splice variants more often preserve partial expression but destabilize interaction surfaces, producing hypomorphic transport defects that are amplified at tissue‐specific vulnerable points [10, 23].

At the organ level, these defects are expressed as neurological, retinal, skeletal, renal, and syndromic manifestations through different thresholds of ciliary transport demand, receptor localization, polarity control, and tissue stress tolerance (Figure 2).

FIGURE 2.

Organ‐level consequences of IFT172 dysfunction across major affected systems. Note: Figure 2 summarizes representative tissue‐specific consequences associated with IFT172 dysfunction across the nervous, retinal, skeletal, and renal systems. In the nervous system, altered ciliary trafficking may impair TrkB‐related signaling and contribute to neurodevelopmental and motor abnormalities. In the retina, defective outer‐segment protein transport and oxidative imbalance are associated with early retinal degeneration. In the skeletal system, disturbed polarity‐related signaling is linked to abnormal craniofacial and skeletal development. In the renal system, mislocalization of membrane and polarity‐associated proteins is associated with tubular dilation and progressive functional decline. This figure is intended as an organ‐level overview of phenotypic consequences rather than a detailed pathway schematic.

At the variant‐to‐mechanism level, the same framework links domain‐level injury to recurring nodes, including IFT‐particle assembly, anterograde/retrograde transition, receptor recycling, signaling imbalance, polarity disruption, and secondary metabolic or oxidative stress. Distinct IFT172 variants may therefore converge on overlapping phenotypes while retaining tissue‐specific manifestations (Figure 3).

FIGURE 3.

Integrative framework linking IFT172 variant classes, mechanistic nodes, and tissue‐specific phenotypes. Note: IFT172 variants can be grouped into severe loss‐of‐function and domain‐altering forms, which disrupt different regions of the protein and impair IFT particle assembly, directional transport, and receptor trafficking. These defects converge on shared mechanistic nodes, including signaling imbalance, polarity disruption, and metabolic/oxidative stress, but are expressed differently across the nervous system, retina, skeletal/renal systems, and syndromic multi‐organ disorders.

The current evidence supports a hierarchy of primary and secondary pathogenic events. The best‐supported primary events are cilia shortening or loss, reduced assembly efficiency, anterograde/retrograde imbalance, and receptor mislocalization. Secondary events, including cell‐cycle disturbance, metabolic stress, oxidative stress, and inflammatory amplification, are biologically plausible but may differ by cell type and mutation context [27, 28]. Phenotypic heterogeneity also reflects modifier genes and genetic background, which can shift pathway thresholds and tissue compensation [16]. This distinction is important for separating established mechanisms from proposed integrative models.

At the signaling level, impaired IFT172 function can alter the spatial distribution of receptors and pathway regulators that require ciliary compartmentalization. Abnormal Hedgehog output may disturb developmental patterning and differentiation programs [29], whereas disruption of Wnt/planar cell polarity (PCP) signaling can impair oriented cell division, epithelial polarity, and tissue symmetry [30, 31]. In addition, altered ciliary receptor positioning can modify how cells receive and integrate local signals, producing qualitative changes in signaling output rather than only a quantitative reduction in transport efficiency [32]. Tissues with high polarity demand, rapid membrane turnover, or strict developmental timing are therefore disproportionately sensitive to IFT172 dysfunction.

Across organ systems, IFT172 dysfunction produces tissue‐dependent vulnerability rather than a uniform clinical phenotype. Neurological involvement is linked mainly to ciliary receptor localization and neurotrophic or polarity signaling; retinal involvement reflects defective outer‐segment cargo delivery with secondary stress in the retinal pigment epithelium (RPE); skeletal involvement is associated with growth‐plate polarity and differentiation timing; and renal involvement is associated with epithelial architecture, polarity maintenance, and metabolic stress (Table 1).

TABLE 1.

Comparison of key mechanistic modules, signaling axes, and major affected organ systems in BBS, JS, and OFD.

Syndrome	Dominant IFT172‐related module	Representative affected signaling/process	Main involved systems (core phenotypes)	Key points on phenotypic variability
BBS (IFT172‐related) [1]	Reduced IFT172 → impaired intraflagellar transport; indirectly affects receptor entry/exit from cilia	BBSome‐mediated GPCR trafficking/clearance (cAMP‐regulated)	Obesity/metabolic traits, kidney disease, retinal degeneration, neurocognitive features	High inter‐individual variability; shaped by genetic background/modifiers
JS‐like (IFT172‐associated) [2]	IFT172 disruption during neurodevelopment → shortened cilia/altered signal integration	Shift in WNT output balance (canonical vs. non‐canonical)	Cerebellar–brainstem/posterior fossa malformations; often ocular/respiratory signs; may include renal/retinal involvement	Severity can vary with the genetic network background
OFD (IFT172‐related cases) [3]	Truncating/splice variants → predicted loss of function (LoF) of IFT172	Models suggest Ift172 deficiency attenuates Hedgehog readouts	Oral–facial–digital anomalies; may include renal/neuro/retinal involvement	High genetic and phenotypic heterogeneity

Note: [13, 22, 33].

Variant‐class interpretation provides a complementary molecular layer for organ‐specific analysis. Nonsense, frameshift, and severe splice variants support a near‐null model characterized by reduced IFT172 expression or truncated protein production, whereas missense and domain‐altering variants more often indicate partial loss of function, interface instability, or weakened coupling between IFT172, IFT‐A, and the BBSome. When compound variants or modifier effects are present, the final phenotype may depend on the broader ciliary network rather than on IFT172 alone (Table 2).

TABLE 2.

Integrated analysis of tissue‐systemic signaling perturbations and phenotypic mechanisms induced by IFT172 mutations.

Tissue system	Key ciliary mechanism	Dysfunction due to IFT172 loss	Dysregulated signaling pathways	Major phenotypes	Synergistic cofactors
Nervous system [1]	Targeted trafficking of TrkB/CREB	Reduced TrkB membrane localization; decreased CREB phosphorylation	BDNF axis; Wnt–PCP	Autism spectrum disorder (ASD), cognitive impairment	IFT88
Retina [2]	Rhodopsin transport; RPE lipid metabolism	Photoreceptor trafficking defects	ABCA4, ROS accumulation, mitochondrial stress	Retinitis pigmentosa (RP), cone–rod dystrophy (CRD), night blindness	CEP290
Skeletal system [3]	Wnt/PCP polarity and osteogenic rhythm	Abnormal Prickle localization; DVL2 dysregulation	β‐catenin; Gli1	Short rib thoracic dysplasia (SRTD), skeletal dysplasia	TMEM67
Renal system [4]	Proximal polarity‐axis regulation; ion‐transport homeostasis	ZO‐1 mislocalization; impaired ROS clearance	AMPK–Nrf2; cAMP/PKA	Renal cysts; progressive kidney dysfunction	DYNC2H1

Note: [10, 34, 35, 36].

Representative IFT172 variants further illustrate how mutation type, domain localization, and functional consequences can guide genotype–phenotype interpretation. Missense variants in the C‐terminal region often highlight interface instability, splice or truncating variants support reduced dosage or truncated‐protein models, and selected compound contexts may be associated with retinal, renal, skeletal, or syndromic disease combinations (Table S1).

Organ‐level vulnerability and variant‐class interpretation should be considered together rather than attributed to a single pathway. The affected organ indicates which ciliary process is most vulnerable, whereas the molecular lesion estimates how strongly IFT172 function is disturbed. This combined framework supports longitudinal surveillance when the initial presentation is incomplete or organ‐restricted.

The distinction between primary and secondary events is particularly important for therapeutic reasoning. A treatment that improves downstream oxidative stress may slow tissue injury but will not necessarily restore IFT‐particle assembly or receptor recycling. Conversely, a strategy that partially restores IFT172 expression or stability may influence several pathways at once, but the magnitude of rescue may differ across organs. The same variant can therefore require different biomarkers in the retina, kidney, or nervous system, even when the upstream gene defect is identical.

Direct evidence for cilia‐independent IFT172 functions remains limited. Abnormalities in cell‐cycle control, cytoskeletal organization, or metabolic stress may be detected outside the cilium, but most are best interpreted as secondary consequences of failed ciliary transport unless experiments specifically separate ciliary localization from extraciliary function. Future studies comparing ciliary‐localization mutants with non‐localizing rescue constructs, cilia‐deficient backgrounds, and time‐resolved assays will be necessary to determine whether stress responses follow or precede transport failure.

2.3. Nervous System: Ciliary Receptor Trafficking and TrkB‐CREB‐Related Neurodevelopment

Neuronal primary cilia concentrate G protein‐coupled receptors (GPCRs) and receptor tyrosine kinases that influence neurogenesis, synaptic maturation, and behavior [33, 37, 38]. IFT172 variants can perturb this compartmentalization and thereby affect brain‐derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB), cyclic adenosine monophosphate (cAMP)‐protein kinase A (PKA)‐cAMP response element‐binding protein (CREB), and Wnt/PCP‐related signaling [39]. In partial‐loss models, IFT172 insufficiency has been linked to anxiety‐like behavior, altered social exploration, and cognitive deficits, supporting a role in neurodevelopmental regulation rather than only gross ciliary morphology [12].

Mechanistically, reduced ciliary or axonal targeting of TrkB can blunt BDNF‐dependent CREB phosphorylation and decrease expression of neurotrophic and synaptic‐plasticity genes such as Arc, Npas4, and Egr1 [40]. Transcriptomic and cellular studies further suggest abnormalities in axon guidance, dendritic‐spine organization, and synaptic‐vesicle recycling. In parallel, disturbed Wnt/PCP signaling during neural progenitor development may contribute to abnormal polarity establishment, radial migration, and cerebellar or brainstem organization, thereby connecting IFT172 dysfunction with JS‐like structural features [41, 42].

Small‐molecule TrkB agonism has shown proof‐of‐concept rescue of selected behavioral and transcriptional readouts in experimental settings, but it remains a preclinical strategy rather than an established therapy [40].

Two interpretive points are important for nervous‐system data. First, neurological phenotypes may arise from developmental patterning defects, impaired receptor localization in mature neurons, or both. Second, behavioral phenotypes in animal models are informative but cannot be directly equated with human neurodevelopmental diagnoses. A balanced interpretation is that IFT172 participates in ciliary signaling programs required for neuronal circuit formation and synaptic plasticity, while clinical expression depends on developmental timing, allele severity, and additional genetic context.

Taken together, these observations support a transport‐centered neurological model in which IFT172‐dependent ciliary trafficking influences TrkB localization, CREB activation, and Wnt/PCP‐related polarity cues. These axes connect molecular transport defects with neuronal differentiation, axon guidance, dendritic‐spine organization, and midline brain development, while leaving room for developmental‐window and allele‐specific variability.

2.4. Retina: Transport Failure With Secondary Lipid, Inflammatory, and Oxidative Modules

The retina is one of the most vulnerable systems in IFT172‐associated disease because photoreceptors require continuous IFT‐dependent delivery of rhodopsin and other phototransduction proteins to the outer segment [43, 44]. IFT172 deficiency produces shortened connecting cilia, disorganized outer‐segment discs, phototransduction‐protein mislocalization, impaired electroretinography responses, and progressive photoreceptor degeneration [10, 21]. These transport defects are the most directly supported initiating events in IFT172‐related retinopathy.

Beyond the primary transport defect, retinal degeneration is best interpreted through an integrative model of secondary retinal pigment epithelium (RPE), lipid, inflammatory, and oxidative stress responses. RPE cells phagocytose shed outer‐segment discs and depend on lipid‐handling systems, including CYP4V2‐linked metabolism, to maintain retinal homeostasis [45, 46, 47]. Available data suggest that IFT172 dysfunction may indirectly disturb metabolic‐regulator localization or stability, favoring cholesterol‐metabolite imbalance and altered liver X receptor (LXR)‐ATP‐binding cassette transporter A1 (ABCA1)‐related responses [48]. Lipid accumulation and RPE stress may then reinforce microglial activation and innate immune signaling such as cyclic GMP‐AMP synthase (cGAS)‐stimulator of interferon genes (STING) signaling in related retinal injury contexts [49, 50] (Figure 4).

FIGURE 4.

Illustration of the multidimensional pathogenesis due to the IFT172 mutation in the retinal system. Note: The left schematic illustrates the spatial relationship between the photoreceptor layer and the retinal pigment epithelium (RPE) under light stimulation, emphasizing that IFT172 mutations primarily compromise homeostatic maintenance of the photoreceptor outer segment and the RPE support unit. The mechanistic diagram on the right summarizes a multi‐level pathological cascade in the retina following IFT172 dysfunction. First, impaired intraflagellar transport leads to insufficient delivery of essential outer‐segment proteins, manifested by failed trafficking of phototransduction‐related proteins such as rhodopsin and PDE6, which in turn causes outer‐segment disorganization and reduced phototransduction capacity. Second, mislocalization of lipid metabolism–related factors in the RPE—particularly CYP4V2 mislocalization—can disrupt cholesterol metabolic pathways and excessively activate the LXR–ABCA1 axis, promoting abnormal lipid efflux and lipofuscin accumulation. Third, lipid deposition and metabolic stress can activate the cGAS–STING immune axis, inducing chronic sterile inflammation and impairing the RPE barrier function. Fourth, aberrant localization of antioxidant enzymes and impaired mitochondrial homeostasis lead to ROS accumulation, accompanied by suppressed Nrf2 responses and mtDNA damage, which further triggers a mitochondria‐associated apoptotic cascade. Arrows indicate the temporal sequence and causal relationships, while dashed lines denote signal amplification and/or feedback regulation. Together, these processes ultimately drive early‐onset retinal degeneration and progressive loss of visual function.

Oxidative stress is also likely to amplify degeneration, but the precise ordering of antioxidant‐enzyme mislocalization, mitochondrial Ca²⁺ imbalance, PINK1/Parkin responses, ASK1‐JNK/p38 activation, nuclear factor erythroid 2‐related factor 2 (Nrf2) dysregulation, and mitochondrial DNA (mtDNA) damage remains incompletely resolved [51, 52, 53, 54]. Therefore, these processes are better interpreted as interconnected secondary stress modules rather than a universally validated stepwise pathway.

Clinically, IFT172‐related retinopathy can present as retinitis pigmentosa, cone‐rod dystrophy, or early visual decline in Mainzer‐Saldino syndrome; progression may be shaped by domain location and compound variants in the broader ciliary network [11, 55]. Photoreceptor degeneration clearly begins with defective transport and outer‐segment instability, but the relative contributions of RPE lipid stress, innate immune activation, mitochondrial damage, and antioxidant‐response failure may vary between models and disease stages. These modules likely interact through feedback loops: failed outer‐segment renewal increases RPE burden, RPE stress can amplify inflammation, and inflammation can intensify oxidative injury. These processes are therefore best interpreted as reinforcing mechanisms rather than as a fixed sequence validated for every IFT172 variant.

These secondary modules have therapeutic relevance without requiring a fully linear causal model. If lipid handling, innate immune activation, or oxidative stress contribute to progression, they may become adjunctive targets for slowing degeneration after the primary transport defect has initiated tissue injury. However, such strategies would be expected to modify stress amplification rather than correct the underlying IFT defect.

Clinically, IFT172‐associated retinopathy can present as retinitis pigmentosa, cone‐rod dystrophy, or Mainzer‐Saldino‐related visual decline. These phenotypes are representative outputs of the same transport‐centered vulnerability. More detailed genotype–phenotype interpretation is most useful when it clarifies domain location, such as C‐terminal defects affecting coupling or transition‐related functions and N‐terminal defects affecting assembly‐related processes.

2.5. Skeletal and Renal Systems: Polarity, Differentiation, and Metabolic Stress

Skeletal and renal phenotypes share a strong dependence on cilia‐mediated polarity, directional growth, and epithelial organization [56] In growth plates, chondrocyte cilia coordinate columnar alignment and differentiation. IFT172 mutations can disturb Wnt5a/Fzd3‐Vangl2 polarity signaling and Hedgehog‐Gli output, producing abnormal growth‐plate patterning, shortened ribs, and skeletal dysplasia [57, 58, 59, 60]. Embryonic models and patient‐derived cells support defects in polarity‐protein localization, ciliary positioning, centrosomal organization, and bone‐matrix production [61, 62, 63].

In the kidney, IFT172 supports apical‐basal polarity, lumen extension, and tubular epithelial alignment [34, 64]. Loss of IFT172 can disrupt ciliary architecture and IFT‐particle assembly and can mislocalize polarity determinants such as ZO‐1, Par3/6, and aPKC, leading to tubule dilation, cyst formation, and declining renal function [35]. Renal involvement may further involve mitochondrial and metabolic stress, but these should be viewed as downstream contributors whose magnitude varies across models. Thus, skeletal and renal manifestations can be unified by a transport‐polarity‐metabolism model in which an initial IFT defect shifts tissue‐patterning thresholds and later amplifies stress responses [65, 66].

Skeletal and renal disease are not simply independent consequences of the same gene. Both tissues depend on oriented growth and epithelial or matrix architecture, but the dominant readout differs: the growth plate displays disturbed columnar organization and differentiation timing, whereas renal tubules display polarity collapse, lumen dilation, and progressive functional decline. This cross‐organ comparison supports a mechanistic model in which IFT172 dysfunction converges on tissue polarity and structural maintenance.

Renal pathology is therefore best interpreted primarily through epithelial architecture rather than through a long list of isolated kidney phenotypes. IFT172 dysfunction can influence tubule shape, epithelial junction organization, ciliary signaling thresholds, and later metabolic stress. This framework helps link early polarity defects with later cystic or fibrotic progression.

The bone‐kidney axis also illustrates why tissue context matters. Both organs are sensitive to polarity disruption, but the timing of injury differs. Skeletal defects often arise during developmental patterning, making later reversal difficult. Renal disease may progress over a longer period as epithelial polarity defects, cystic remodeling, and metabolic stress accumulate. Therefore, the same IFT172 variant may require early developmental interpretation for skeletal findings and longitudinal surveillance for renal function.

Likewise, the skeletal subsection emphasizes growth‐plate polarity and differentiation timing. Chondrocytes require coordinated ciliary signaling to align within columnar structures, and disruption of Wnt/PCP or Hedgehog‐related output can impair longitudinal growth. By presenting skeletal disease through polarity and patterning rather than through multiple rare phenotypic labels, the section remains integrated with the kidney discussion and with the variant‐class framework.

2.6. Syndromic Phenotypes and Genetic‐Network Effects

IFT172‐associated syndromes reflect multi‐system expression of the same ciliary transport defect. In BBS, IFT172, historically referred to as BBS20, contributes to BBSome‐associated receptor trafficking; the BBSome regulates entry, retrieval, and clearance of ciliary membrane proteins, including GPCRs [33, 67]. Clinically, BBS shows wide intra‐ and interfamilial variability, especially in renal, retinal, metabolic, and neurocognitive involvement, indicating that genotype alone does not fully predict phenotype [68, 69]. In JS, biallelic IFT172 variants can be associated with cerebellar‐brainstem malformations, including the molar‐tooth sign, through disruption of cilia‐dependent neurodevelopmental polarity signaling [13, 70].

In the orofaciodigital spectrum, IFT172 splice or loss‐of‐function variants have been reported in cases with craniofacial, digital, renal, and retinal manifestations [71]. Across syndromes, the clinical picture is shaped by the interaction between the core IFT172 variant and the broader ciliary network, including additional variants or modifiers in genes such as CEP290, DYNC2H1, TTC21B, and TMEM67 [72].

The syndromic spectrum can be interpreted as a comparative model rather than a catalogue of unrelated rare conditions. BBS emphasizes BBSome‐associated receptor recycling and marked phenotypic variability. JS emphasizes cilia‐dependent neurodevelopmental patterning. The OFD spectrum emphasizes splice or loss‐of‐function variants affecting craniofacial and digital development. These disease categories overlap because they share an upstream IFT defect, but they differ in the dominant tissue module and developmental window through which that defect is amplified.

Spatially restricted Wnt and Hedgehog signaling provides a schematic bridge between structural IFT failure and tissue phenotypes. Both pathways depend on the movement of receptors, adaptors, and transcriptional regulators around the ciliary compartment. In Wnt‐associated contexts, altered receptor or adaptor localization can shift canonical beta‐catenin output or non‐canonical Wnt/PCP signaling, affecting cell alignment and developmental polarity. In Hedgehog‐associated contexts, defective ciliary entry and turnover of PTCH1, SMO, and GLI‐related components can disturb GLI activator‐repressor balance. In the growth plate, renal epithelium, craniofacial mesenchyme, and neural midline structures, Wnt/PCP and Hedgehog outputs may combine with GPCR‐cAMP and BBSome‐dependent receptor‐recycling defects; these relationships are best interpreted as compartmentalized trafficking events rather than as a single linear pathway (Figure 5).

FIGURE 5.

IFT172‐associated ciliary trafficking events linked to Wnt and Hedgehog signaling. Note: The numbered steps indicate representative signaling events associated with cilium‐dependent trafficking and pathway output. Wnt‐related events: (1) ligand–receptor engagement at the ciliary/periciliary region and recruitment of downstream components such as Dishevelled; (2) stabilization and accumulation of β‐catenin following attenuation of the destruction complex; (3) nuclear translocation of β‐catenin and activation of TCF/LEF‐dependent transcription. Hedgehog‐related events: (4) ciliary trafficking and activation of SMO following relief of PTCH‐mediated inhibition; (5) activation of Gli‐dependent signaling, including dissociation of inhibitory complexes and formation of transcriptionally active Gli species; (6) in the absence of Hedgehog signaling, kinase‐dependent processing of Gli3; (7) generation of the repressor form Gli3R and repression of Hedgehog target genes. This schematic summarizes how altered IFT172‐dependent ciliary transport may influence Wnt‐ and Hedgehog‐related signaling outputs that are relevant to neurodevelopmental, craniofacial, renal, retinal, and skeletal manifestations in ciliopathies.

Consistent nomenclature is clinically important. IFT172 is used as the primary gene name, with BBS20 retained only once as a historical alias in the BBS context. This convention prevents the impression that IFT172 and BBS20 represent separate genes or independent concepts and improves readability for readers who move between older BBS nomenclature and current IFT gene terminology.

3. Diagnostic and Therapeutic Implications

3.1. Diagnostic Stratification and Clinical Surveillance

For diagnosis, the main practical value of an IFT172‐centered framework is not simply listing phenotypes, but linking variant class and domain location to organ surveillance priorities. Severe truncating or splice‐disrupting variants warrant careful evaluation for syndromic involvement, whereas hypomorphic or domain‐altering variants may produce later‐onset or organ‐biased disease. Because phenotypic severity can be modified by the wider ciliary gene network, clinical interpretation should integrate genotype, domain‐level predictions, segregation data, and organ‐specific findings rather than relying on a single variant label [14, 15].

Clinical surveillance should therefore follow the biological logic of the variant rather than a fixed organ checklist alone. For a child with early retinal degeneration, renal function and skeletal growth may still require longitudinal evaluation even when initial imaging is unremarkable. For a patient presenting with skeletal dysplasia or renal cystic change, retinal electrophysiology, neurodevelopmental assessment, and family segregation analysis can help determine whether the phenotype is isolated or syndromic. This approach also accommodates age‐dependent penetrance because some manifestations emerge only after the developmental or metabolic burden of ciliary dysfunction has accumulated over time.

3.2. Therapeutic Feasibility and Translational Endpoints

Therapeutic interpretation requires clear feasibility boundaries. Many skeletal and craniofacial abnormalities are established during embryogenesis and are unlikely to be reversed postnatally. In contrast, retinal degeneration and selected renal or neurological functional impairments may offer longer windows in which preserving function or slowing progression is realistic [73, 74] For autosomal‐recessive loss‐of‐function disease, gene augmentation is conceptually attractive, but the large IFT172 coding sequence exceeds standard single‐adeno‐associated virus (AAV) capacity and may require split‐vector or higher‐capacity systems with unresolved efficiency and safety issues [75, 76]. Gene editing may be useful for specific point mutations but is unlikely to serve as a universal approach because pathogenic IFT172 variants are highly diverse and tissue delivery to the retina, kidney, and brain remains challenging [77].

For splice variants, antisense oligonucleotide‐mediated splice correction may bypass coding‐sequence size limits and could be useful when partial restoration is sufficient to cross a functional threshold [78]. For missense or hypomorphic alleles, mechanism‐guided screening for proteostasis, complex‐assembly, or receptor‐trafficking rescue is a rational but still early‐stage direction. Pathway modulation, including Hedgehog (Hh), Wnt, GPCR‐cAMP, or neurotrophic signaling, is best positioned as context‐dependent compensation rather than definitive etiologic correction.

For clinical translation, three types of endpoints are especially important. Structural endpoints include ciliary length, IFT‐particle entry, train frequency, and localization of receptors or outer‐segment cargoes. Functional cellular endpoints include pathway reporters for Hh, Wnt, GPCR‐cAMP, and neurotrophic signaling. Organ‐level endpoints include visual function, renal function, neurodevelopmental readouts, and skeletal growth measures. A candidate intervention should ideally improve at least one upstream ciliary endpoint and one organ‐relevant functional endpoint; otherwise, an apparent pathway change may not represent disease modification.

From a clinical perspective, this endpoint hierarchy helps distinguish mechanistic rescue from phenotypic rescue. Restoration of ciliary length alone may not indicate functional recovery if receptor localization, IFT‐train turnover, or cargo delivery remains abnormal. Conversely, improvement in a downstream pathway marker may represent partial compensation without correction of the upstream transport defect. For IFT172‐associated disorders, the most convincing preclinical evidence will therefore combine structural ciliary readouts, dynamic transport assays, pathway‐output measurements, and organ‐relevant functional outcomes. This requirement is particularly important in the retina, kidney, and nervous system, where delayed progression may reflect both primary transport failure and secondary stress amplification. A therapeutic candidate that modifies only one layer of this chain may still be useful as an adjunctive strategy, but disease‐modifying claims require evidence across multiple levels of the transport‐to‐phenotype axis. Molecular rescue, cellular rescue, and clinical rescue should therefore be reported as related but distinct levels of evidence, especially when short‐term pathway normalization is used to infer long‐term protection. This distinction can reduce overinterpretation and improve comparability across future IFT172 models. It is also consistent with cautious evaluation of rare‐disease mechanisms where sample size is often limited.

IFT172‐specific therapies are not yet clinically established. Gene augmentation, editing, splice correction, proteostasis rescue, and downstream pathway modulation represent strategies at different levels of feasibility. Their translational value will depend on whether they improve upstream ciliary transport or receptor localization and whether those changes translate into organ‐level benefit.

For gene augmentation, the central barrier is not the concept of replacing IFT172 but the practicality of delivering a large coding sequence to the correct tissue at sufficient levels. Ocular delivery is more tractable than systemic kidney or brain delivery, but even in the eye, dual‐vector or high‐capacity approaches require careful evaluation of recombination efficiency, expression uniformity, and long‐term safety. For editing strategies, the key limitation is variant diversity: a highly specific editor may be attractive for a founder or recurrent point mutation but cannot easily address the full allelic spectrum. For splice correction, the most realistic scenario is partial restoration in alleles where corrected transcript production can cross a functional threshold.

Small‐molecule and pathway approaches require equally strict criteria. Proteostasis or assembly‐enhancing screens may be most relevant for missense variants with residual protein, whereas downstream pathway modulation may be more useful when structural rescue is not feasible. In both cases, quantitative readouts are more informative than broad therapeutic optimism. Candidate interventions need to be tested against ciliary transport, receptor localization, pathway output, and organ‐specific function, because improvement in only one downstream marker may not translate into meaningful disease modification.

In diagnostic practice, the same logic supports tiered follow‐up. A patient with a truncating variant and early retinal disease requires evaluation for renal and skeletal involvement even if these findings are not initially prominent. A patient with a missense variant and mild or isolated retinal disease still warrants review for subtle extraocular features, but counseling should acknowledge uncertainty rather than assuming inevitable multisystem progression. This genotype‐informed but phenotype‐sensitive approach is more useful than assigning fixed outcomes to individual variants.

Such an approach is also compatible with genetic counseling: uncertainty should be communicated as a feature of current evidence, not as a failure of interpretation, because IFT172‐associated disease often reflects interactions among allele severity, developmental timing, and organ‐specific reserve. This caution improves clinical readability substantially.

Diagnostic interpretation should remain dynamic. As additional family members are tested, as renal or retinal findings evolve, and as new functional data become available, the assessment of a given IFT172 variant may change. For this reason, clinical interpretation benefits from surveillance, segregation analysis, domain‐level assessment, and functional validation rather than a single static label for each variant.

4. Conclusion

IFT172 is a central IFT‐B organizer that links transport‐particle assembly, train remodeling, receptor trafficking, and cilia‐dependent signaling. The most consistent primary consequences of IFT172 dysfunction are defective IFT‐train assembly, impaired cargo localization, and altered directional transition at the ciliary tip. Tissue‐specific phenotypes then emerge because the nervous system, retina, skeleton, and kidney differ in ciliary trafficking demand, signaling thresholds, developmental timing, and stress tolerance. A balanced interpretation should therefore separate established transport defects from secondary or proposed mechanisms involving lipid metabolism, inflammation, oxidative stress, and metabolic remodeling. This synthesis supports a practical diagnostic model based on variant class, structural domain, and organ vulnerability, while emphasizing that therapeutic strategies remain exploratory and must be advanced through variant‐ and tissue‐specific validation.

Future progress will depend on linking variant‐level structural effects with quantitative ciliary readouts and organ‐level outcomes. Useful experimental endpoints include train entry, transition‐state remodeling, receptor localization, photoreceptor cargo transport, renal epithelial polarity, and growth‐plate organization. Integrating these endpoints with longitudinal clinical data will improve genotype–phenotype interpretation and therapeutic stratification.

Genetic diagnosis should combine variant classification with organ surveillance. Severe loss‐of‐function variants warrant careful evaluation for syndromic involvement, whereas hypomorphic or domain‐altering variants require attention to organ‐biased disease and subtle extraocular findings. Modifier variants and family‐specific background effects should be considered when phenotype severity does not match the predicted allele class.

For translational development, the most useful path is not a single universal therapy but a tiered strategy that matches allele class, tissue window, delivery feasibility, and measurable ciliary rescue. Gene or splice‐correction strategies may be prioritized when the molecular lesion is well defined and delivery is feasible, whereas proteostasis or pathway‐based strategies may be more appropriate for hypomorphic alleles or tissues in which etiologic correction remains technically difficult.

Author Contributions

Xiaoqing Wang and Lei Zhang design the work. Dandan Chen designed the manuscript. Yuhan Wang, Pengyao Ren, Yangyang Zhou, and Chun Zhang wrote the draft. Waner Wang, Jiayi Geng, and Yitong Chai revised the manuscript. Jiajia Xie, Shuangjie Li, and Zhongyi Yan conceptualized and generated the figures and tables.

Funding

This work was supported by the Kaifeng City Science and Technology Research Program (grant numbers 2053168); the Henan Province Science and Technology Research Project (grant numbers 262102310199); National Natural Science Foundation of China (grant numbers 82401779); Key Scientific Research Project of Higher Education of Henan Province (grant number 23A310009) and the key scientific research project of Henan Province (grant number 242102311182).

Ethics Statement

The authors have nothing to report.

Consent

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Table S1: Correlation Between IFT172 Mutation Types, Structural Domains, Functional Defects, and Clinical Phenotypes.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.