TRPV4 – Autosomal Dominant Brachyolmia

Autosomal dominant brachyolmia (Type 3, MONDO:0007232) is a skeletal dysplasia characterized by disproportionate short stature, platyspondyly, and progressive scoliosis. TRPV4 (HGNC:18083) encodes a Ca²⁺-permeable, non-selective cation channel widely expressed in bone and cartilage. Heterozygous missense variants in TRPV4 were first implicated in AD brachyolmia in a large Swedish kindred, revealing early spine involvement and chronic pain, with radiographic changes evident by school age (PMID:24677493).

Genetic evidence supports an autosomal dominant inheritance mode. In the Swedish family, 11 affected individuals harbored the recurrent c.1847G>A (p.Arg616Gln) variant, segregating with disease across three generations (PMID:24677493). Independent confirmation in two siblings demonstrated the same mutation correlating with transient metaphyseal striations and platyspondyly (PMID:28601949). Additionally, two unrelated brachyolmia probands in a multi-family spectrum study further underscore pathogenicity (PMID:21658220). The total of 13 affected relatives across three families reflects robust segregation.

Clinically, affected individuals present in early childhood with short trunk growth that accelerates spinal deformity over time. Common findings include scoliosis (HP:0002650), platyspondyly (HP:0000926), and disproportionate short stature (HP:0003498). Growth may be normal in early years but deteriorates with age due to spinal involvement, leading to chronic pain in spine and hips.

The genetic spectrum in brachyolmia is restricted to heterozygous TRPV4 missense variants. The c.1847G>A (p.Arg616Gln) change is recurrent and lies within a conserved cholesterol-interaction motif. Other TRPV4 channelopathies involve hotspot codons (e.g., p.Pro132Leu, p.Arg206Cys) but have distinct phenotypes.

Functional assays demonstrate that the p.Arg616Gln mutation abolishes TRPV4 interaction with membrane cholesterol, reducing lipid-raft localization in osteogenic and neuronal cell models. GST-pulldown and FRAP experiments show loss of high-molecular weight complex formation and altered channel mobility, suggesting impaired membrane trafficking and constitutive dysregulation of Ca²⁺ influx (PMID:31387748).

The mechanism of pathogenesis appears to involve altered channel regulation rather than simple gain- or loss-of-function, leading to perturbed chondrocyte and osteoblast signaling. Cholesterol-dependent trafficking defects likely contribute to abnormal bone morphogenesis and long-term morbidity in AD brachyolmia.

No studies have refuted the TRPV4–brachyolmia link. However, phenotypic overlap with other TRPV4-mediated dysplasias suggests a spectrum rather than discrete entities. Further natural history studies would refine prognosis and management.

In summary, heterozygous TRPV4 missense variants, particularly c.1847G>A (p.Arg616Gln), show strong genetic and moderate functional evidence for autosomal dominant brachyolmia. Genetic testing for TRPV4 variants enables definitive diagnosis, informing surveillance for progressive spinal involvement and guiding family counseling.

References

• American journal of medical genetics. Part A • 2014 • Autosomal dominant brachyolmia in a large Swedish family: phenotypic spectrum and natural course. PMID:24677493
• Skeletal radiology • 2017 • Autosomal dominant brachyolmia: transient metaphyseal striations. PMID:28601949
• 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
• Biochemical and biophysical research communications • 2019 • TRPV4 expresses in bone cell lineages and TRPV4-R616Q mutant causing Brachyolmia in human reveals "loss-of-interaction" with cholesterol. PMID:31387748

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