Ferroptosis, driven by uncontrolled peroxidation of membrane phospholipids, is distinct from other cell death modalities because it lacks an initiating signal and is surveilled by endogenous antioxidant defenses. Glutathione peroxidase 4 (GPX4) is the guardian of ferroptosis, although its membrane-protective function remains poorly understood. Here, structural and functional analyses of a missense mutation in GPX4 (p.R152H), which causes early-onset neurodegeneration, revealed that this variant disrupts membrane anchoring without considerably impairing its catalytic activity. Spatiotemporal Gpx4 deletion or neuron-specific GPX4R152H expression in mice induced degeneration of cortical and cerebellar neurons, accompanied by progressive neuroinflammation. Patient induced pluripotent stem cell (iPSC)-derived cortical neurons and forebrain organoids displayed increased ferroptotic vulnerability, mirroring key pathological features, and were sensitive to ferroptosis inhibition. Neuroproteomics revealed Alzheimer's-like signatures in affected brains. These findings highlight the necessity of proper GPX4 membrane anchoring, establish ferroptosis as a key driver of neurodegeneration, and provide the rationale for targeting ferroptosis as a therapeutic strategy in neurodegenerative disease. The autosomal dominant TRPV4-related disorders include two principal types: neuromuscular disorders and skeletal dysplasias. Affected individuals typically have either neuromuscular or skeletal manifestations, although overlapping phenotypes can occur. There is a wide range of phenotypic severity. In the mildest of the autosomal dominant TRPV4-related disorders life span is normal; in the most severe it is shortened. The three clinically recognized autosomal dominant neuromuscular disorders are Charcot-Marie-Tooth disease type 2C, scapuloperoneal spinal muscular atrophy, and congenital distal spinal muscular atrophy. Clinical overlap between these phenotypes does occur. These neuromuscular disorders are characterized by a motor-predominant, non-length-dependent peripheral neuropathy or motor neuronopathy with a wide range in age of onset, from congenital to late adult. Additional common features include laryngeal dysfunction (i.e., vocal fold paresis causing voice change and/or inspiratory stridor), diaphragm weakness (orthopnea), scoliosis, bilateral sensorineural hearing loss, and joint contractures. The five autosomal dominant skeletal dysplasias are (from mildest to most severe) familial digital arthropathy with brachydactyly, brachyolmia, spondylometaphyseal dysplasia (Kozlowski type), spondyloepimetaphyseal dysplasia (Maroteaux type), and metatropic dysplasia. All TRPV4-related skeletal dysplasias are characterized by brachydactyly; the four most severe forms have short stature that varies from mild to severe with progressive spinal deformity and involvement of the long bones and pelvis. The diagnosis of an autosomal dominant TRPV4-related disorder is established in a proband who has characteristic clinical and neurophysiologic findings, radiographic findings in the skeletal dysplasias, and a heterozygous TRPV4 pathogenic variant identified by molecular genetic testing. Treatment of manifestations: Treatment is focused on symptom management. Affected individuals are often evaluated and managed by a multidisciplinary team that may include neurologists, physiatrists, orthopedic surgeons, otologists/audiologists, laryngologists, pulmonologists, geneticists, and physical and occupational therapists. This multidisciplinary team will determine the best treatment options for supportive care, prevention of obesity, and management of pain and depression. For neuromuscular disorders, additional treatment includes special shoes with good ankle support, shoe orthotics, ankle-foot orthoses / knee-ankle-foot orthoses, surgery for severe foot deformities, mobility devices, and exercise as tolerated; management of kyphoscoliosis per orthopedist; management of tethered spinal cord per neurosurgeon; laryngeal surgery for vocal cord paresis (in some individuals, vocal fold lateralization or tracheostomy); speech therapy; and respiratory therapy including noninvasive ventilatory support as needed. For skeletal dysplasias, additional treatment includes physical therapy/exercise and heel cord stretching to maintain function; surgical intervention when kyphoscoliosis compromises pulmonary function and/or causes pain and/or when upper cervical spine instability and/or cervical myelopathy are present. Surveillance: For neuromuscular disorders, annual neurologic examination, physical therapy assessment, otolaryngology evaluation of laryngeal function, dynamic breathing chest radiograph, pulmonary function tests, sleep study, hearing assessment, and musculoskeletal evaluation; assessment of weight, height, and weight-for-height or body composition to diagnose obesity at each visit. For skeletal dysplasias, annual evaluation for joint pain and scoliosis; assessment for odontoid hypoplasia before a child reaches school age and before surgical procedures involving general anesthesia; annual hearing assessment; and assessment of weight, height, and weight-for-height at each visit. Agents/circumstances to avoid: Obesity, as it makes walking more difficult. For neuromuscular disorders, avoid diabetes and neurotoxic medications; upper respiratory tract infections can cause vocal fold swelling and worsen upper airway obstruction. For skeletal dysplasias, avoid extreme neck flexion and extension (in those with odontoid hypoplasia); activities that place undue stress on the spine and weight-bearing joints. Pregnancy management: Ideally a woman with an autosomal dominant TRPV4-related disorder would seek consultation from a high-risk obstetrician or maternal-fetal medicine specialist to evaluate risk associated with pregnancy and delivery. By definition, autosomal dominant TRPV4-related disorders are inherited in an autosomal dominant manner. Because the most severe TRPV4-related skeletal phenotypes can be lethal in childhood (or in utero), children with these phenotypes typically have a de novo pathogenic variant and unaffected parents. Individuals with less severe skeletal phenotypes or neuromuscular phenotypes often have the disorder as the result of a TRPV4 pathogenic variant inherited from a heterozygous parent (de novo pathogenic variants have also been described in individuals with these phenotypes). Each child of an individual with an autosomal dominant TRPV4-related disorder has a 50% chance of inheriting the TRPV4 pathogenic variant. Specific phenotype, age of onset, and disease severity cannot be accurately predicted because of reduced penetrance and highly variable expressivity. However, in general, a child who inherits a TRPV4 pathogenic variant associated with neuromuscular disease or skeletal dysplasia from an affected parent is likely to have a similar overall phenotype as the parent, although the age of onset and severity may be quite distinct. Once the TRPV4 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

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. The online version contains supplementary material available at 10.1186/s13023-025-04070-y. Spondylometaphyseal dysplasia, corner fracture type (SMDCF) is a skeletal dysplasia characterized by short stature and a waddling gait in early childhood. Short stature may be present at birth or develop in early infancy. Individuals may present with short limbs and/or short trunk. Radiographic features include enlargement and corner fracture-like lesions of the metaphyses, developmental coxa vara, shortened long bones, scoliosis, and vertebral anomalies. Limited joint mobility and chronic pain are common. Vision impairment and glaucoma have been reported. The diagnosis of SMDCF is established in a proband with characteristic clinical and radiographic features including short stature, corner fracture-like lesions, developmental coxa vara, and vertebral anomalies. Identification of a heterozygous pathogenic variant in COL2A1 or FN1 by molecular genetic testing can confirm the diagnosis if radiographic features are inconclusive. Treatment of manifestations: Standard treatment for scoliosis per orthopedist; surgical treatment for coxa vara, genu valgum or varum, bowing of the tibia, leg length discrepancy, atlantoaxial instability per orthopedist; management of mobility issues and chronic joint pain by orthopedist and/or physiatrist and physical therapist; management of vision impairment and glaucoma per ophthalmologist; management of hypertension per internist and/or cardiologist; management of psychosocial issues by a psychotherapist and/or referral to support groups. Surveillance: Annual evaluation by an orthopedist and/or physiatrist for scoliosis, other orthopedic complications, mobility issues, and chronic pain. Annual evaluation of intraocular pressure and blood pressure in individuals with FN1-related SMDCF. Annual screening for psychosocial issues. Agents/circumstances to avoid: Contact sports if atlantoaxial instability is present; activities that cause joint strain in those with joint pain. Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt treatment for orthopedic and ophthalmologic complications. SMDCF is inherited in an autosomal dominant manner. An individual with SMDCF may have an affected parent or, somewhat more frequently, may have the disorder as the result of a de novo pathogenic variant. Each child of an individual with SMDCF has a 50% risk of having SMDCF. If the SMDCF-causing pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Glutathione peroxidase 4 (GPX4) is distinguished from other members of the GPX family as being the enzyme capable of reducing phospholipid hydroperoxides within cellular membranes and therefore protecting cells from ferroptosis, a form of iron-driven cell death involving lipid peroxidation. We previously identified a homozygous point mutation in the GPX4 gene, resulting in an R152H coding mutation and a substantial loss of GPX4 enzymatic activity, in patients with Sedaghatian-type spondylometaphyseal dysplasia (SSMD), an ultrarare progressive disorder. To explore whether selective binding and correction of the loss of enzyme activity observed with this variant is possible, we screened 2.8 billion compounds in a DNA-encoded chemical library and identified compounds with remarkably selective binding affinities with the R152H variant (GPX4R152H) over wild-type (GPX4WT). Our structural optimization of these compounds led to the identification of analogues with improved potency for R152H GPX4. The most promising compounds selectively restored the enzyme activity of GPX4R152H and specifically increased the viability of fibroblast and lymphoblast cells developed from an SSMD patient with the homozygous R152H variation but not control cells from a healthy parent or HEK293T cells undergoing ferroptosis induced by a wild-type GPX4 inhibitor. This approach represents a low-cost, high-throughput, and generalizable approach to identify targeted small-molecule therapeutics for missense variants, which features the potential to be broadly applied to diseases that bear point mutations on crucial proteins, including cancers.

Ciliopathies are associated with a range of phenotypes including retinal degeneration and skeletal abnormalities. We present a retrospective study of 49 patients with variants in Cilia and Flagella Associated Protein 410 (CFAP410) from multiple ophthalmic centers across the world. Common clinical features included early-onset reduced visual acuity, photophobia, and delayed light-to-dark adaptation. A cone-rod dystrophy pattern was observed roughly two times more commonly than rod-cone dystrophy. A minority of patients (22.4%) presented with skeletal abnormalities consistent with axial spondylometaphyseal dysplasia (SMDAX). Patients with the most severe ophthalmic and skeletal phenotypes had disease-associated variants within conserved leucine-rich regions of CFAP410, and the structural effects of these variants were modelled using ChimeraX. This report furthers our understanding of CFAP410-associated clinical phenotypes such as retinal dystrophy and skeletal dysplasia.