TRPV4異常症

BACKGROUND AND OBJECTIVES: Spinal muscular atrophy (SMA) is a group of genetically heterogeneous motor neuron disorders characterized by progressive, predominantly proximal weakness. Non-5q SMA refers to forms occurring without SMN1 pathogenic variants or deletions. More than half of non-5q SMA cases remain genetically unresolved, and muscle MRI may reveal characteristic patterns supporting diagnosis. METHODS: We retrospectively analyzed multicenter data from adults presenting with chronic, progressive, motor-predominant weakness, beginning proximally in the upper or lower limbs, with exclusive or predominant motor involvement on nerve conduction studies and neurogenic changes on EMG. Whole-body MRI was qualitatively graded (Mercuri scale, 42 paired muscles) and quantitatively analyzed in the lower limbs. RESULTS: Among 28 patients (median age 46 [26-50] years), 23 (82.1%) carried pathogenic variants in 13 genes, most commonly VWA1 (n = 5), TRPV4 (n = 4), and VRK1 and DYNC1H1 (n = 3 each). Distinct and reproducible MRI patterns were identified in VRK1-related, DYNC1H1-related, and VWA1-related cases. In VRK1-related SMA, the pattern combined upper limb and iliopsoas sparing with severe gluteal involvement, diffuse thigh involvement, and relative preservation of the posterior tibialis and medial gastrocnemius despite early calf involvement. DYNC1H1-related cases were characterized by sparing of the gluteus maximus, isolated adductor magnus involvement, predominant anterior thigh involvement with marked long head of biceps femoris involvement, and severe triceps surae involvement. In VWA1-related SMA, the pattern included selective gluteus maximus and quadriceps involvement with iliopsoas, gracilis, and sartorius preservation, and predominant peroneal involvement with relative extensor digitorum longus sparing. In TRPV4-related SMA, patterns of muscle involvement were heterogeneous, but the sternocleidomastoid was severely affected in 2 of 4 patients, whereas this muscle remained unaffected in all other cohort members. DISCUSSION: Whole-body muscle MRI appears to be a valuable diagnostic tool for non-5q SMA. Gene-specific imaging signatures, particularly for VRK1, DYNC1H1, and VWA1, can guide targeted genetic testing and support interpretation of variants of uncertain significance. Sternocleidomastoid involvement may represent a specific marker of TRPV4-related SMA. However, confirmation in larger cohorts is needed, although this is constrained by the rarity of these disorders.

PURPOSE: Osteocytes are force-sensitive cells possessing a complex lacunar-canalicular system (LCS), embedded within a piezoelectric bone matrix. TRPV4, as a key mechanosensor, plays a crucial role in osteocyte mechanotransduction and related bone disorders. However, the mechanisms underlying its force sensing, mechanical signaling pathways, and biomechanical response remain poorly understood. METHODS: To address this issue, this study established a finite element model incorporating multiple mechanosensors-including bone matrix, LCS, osteocytes, and TRPV4-based on the piezoelectric effect. By integrating the multiphysics coupling of solid mechanics, fluid mechanics, and electric fields to simulate the complex effects on osteocytes, the model calculated stress, strain, and fluid shear stress (FSS) on TRPV4. RESULTS: Result indicate that piezoelectricity significantly increases stress and strain in TRPV4, particularly FSS. Biomechanical parameters of TRPV4 exhibit significant variations across different locations, with the highest stress levels observed at the cell processes (Maximum increase of approximately 300%). Stress distribution patterns also differ across distinct regions, while stress concentration in TRPV4 primarily occurs in its transmembrane domain and ion channel regions. This study reveals that upon coupling with primary cilia and RhoA, the mechanical response mechanism of TRPV4 undergoes significant alteration. TRPV4 exhibits greater sensitivity to fluid shear stress, whereas Piezo1 responds more strongly to membrane stress. CONCLUSIONS: This study elucidates the microscopic mechanical response mechanism and gating activation mechanism of TRPV4 within complex bone cell environments. It clarifies the interaction mechanisms between TRPV4 and other cellular structures, providing a research pathway for understanding bone cell mechanical transduction mechanisms and complex interactions across multiple scales. This work offers theoretical insights into the pathogenesis and therapeutic approaches for TRPV4-related bone disorders.

Dominant mutations in the calcium permeable ion channel TRPV4 (transient receptor potential vanilloid 4) typically result in skeletal dysplasia or peripheral neuromuscular disease. However, the full spectrum of TRPV4-related phenotypes remains incompletely defined. This study systematically reviewed the clinical and genetic features of 10 Chinese patients harboring various TRPV4 variants. In the cohort, six patients were diagnosed with spondylometaphyseal dysplasia Kozlowski type (SMDK) and four patients with metatropic dysplasia (MD). The most common features involved spinal deformity (platyspondyly, kyphosis or scoliosis), and lower-limb malalignments (genu varum, genu valgum, or leg-length discrepancy). Two patients with MD had neurological deficits. The R594H and P799R substitutions were the most recurrent variants in our study. A novel variant (c.1628T>G, p.L543R) in the S2-S3 loop was identified. The study seeks to improve diagnostic precision by combining genetic and radiographic assessment, and highlights the importance of early spinal surveillance and multidisciplinary care to prevent neurological complications underlying TRPV4-mediated disorders.

Spondylometaphyseal Dysplasia, Kozlowski Type (SMDK) is an autosomal dominant skeletal disorder characterized by marked scoliosis, platyspondyly, overfaced pedicles, and mild metaphyseal changes. Pathogenic variants in TRPV4, which encodes a calcium-permeable nonselective cation channel, are known to underlie SMDK. In this study, we identified a previously unreported missense variant in NM_021625.5(TRPV4): c.2354G > C (p.Trp785Ser), in a patient clinically diagnosed with SMDK. This variant affects a highly conserved residue and is predicted to alter protein conformation. Functional validation through cellular experiments revealed that the p.W785S substitution markedly reduces agonist-induced calcium influx and membrane currents, indicating a loss-of-function effect on TRPV4 channel activity. This deviates from the typical gain-of-function paradigm observed in most TRPV4-related skeletal dysplasias and may explain the relatively milder phenotype in our case. Our findings establish p.W785S as a novel pathogenic variant and highlight loss of TRPV4 activity as an alternative mechanism contributing to disease pathogenesis in SMDK.