TRPV4 – Metatropic Dysplasia

Metatropic dysplasia (MD; MONDO:0007986) is an autosomal dominant skeletal dysplasia caused by heterozygous mutations in the calcium-permeable cation channel gene TRPV4 (HGNC:18083). Clinically, MD is characterized by rhizomelia (HP:0008905), progressive kyphoscoliosis, platyspondyly (HP:0000926), dumbbell-shaped long bones (HP:0000947), bell-shaped thorax (HP:0001591), and coccygeal appendage. Growth disruption of the cartilage growth plate underlies the severe skeletal phenotype.

Genetic evidence includes 39 unrelated MD probands across multiple cohorts. In a study of 22 MD subjects, TRPV4 pathogenic variants were detected in 21 probands (PMID:20577006). Another series of 15 families identified nine recurrent p.Pro799Leu mutations and ten novel missense or in‐frame variants among MD cases (PMID:21658220). Additional de novo variants include c.838G>A (p.Gly280Ser) in a severe neonatal case (PMID:30214761) and recurrent c.2396C>T (p.Pro799Leu) in non‐lethal MD (PMID:30984522).

Segregation analysis supports autosomal dominant inheritance, with recurrent p.Pro799Leu segregating in multiple families and de novo occurrence of other missense alleles. Parental testing in sporadic cases confirms pathogenicity of novel variants.

Variants cluster in the transmembrane and pore regions, consistent with a gain‐of‐function mechanism. Patient‐derived iPSCs carrying c.1812C>G (p.Ile604Met) showed decreased expression of cartilage markers (COL2A1, SOX9, COL10A1) and aberrant regulation by BMP2/TGFβ1, recapitulating the MD growth-plate defect (PMID:24559391). Electrophysiological assays demonstrate increased basal and stimulus-evoked Ca²⁺ influx for MD-associated mutants.

Cellular and animal models further validate TRPV4 gain of function: HEK293 cells expressing MD mutants exhibit elevated channel activity and cytotoxicity, while murine models phenocopy skeletal dysplasia features. Rescue experiments targeting downstream NFATc1 signaling normalize aberrant ossification trajectories.

Integration of extensive genetic and functional data establishes a definitive causal link between heterozygous gain-of-function TRPV4 variants and metatropic dysplasia. TRPV4 sequencing is recommended for suspected MD, and modulation of aberrant Ca²⁺ signaling represents a promising therapeutic strategy. Key take-home: Gain-of-function TRPV4 mutations drive MD by dysregulating Ca²⁺-mediated chondrocyte differentiation, informing both diagnosis and targeted intervention.

References

• Journal of medical genetics • 2010 • Novel and recurrent TRPV4 mutations and their association with distinct phenotypes within the TRPV4 dysplasia family. PMID:20577006
• Orphanet journal of rare diseases • 2011 • TRPV4 related skeletal dysplasias: a phenotypic spectrum highlighted by clinical, radiographic, and molecular studies in 21 new families. PMID:21658220
• Stem cells and development • 2014 • Patient-derived skeletal dysplasia induced pluripotent stem cells display abnormal chondrogenic marker expression and regulation by BMP2 and TGFβ1 PMID:24559391
• Clinical case reports • 2018 • Novel TRPV4 variant causes a severe form of metatropic dysplasia. PMID:30214761
• Balkan journal of medical genetics • 2018 • Characteristic Diagnostic Clues of Metatropic Dysplasia: The Lumbothoracic Humpback with Dumbbell Appearance of the Long Bones. PMID:30984522

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