De novo TRPV4 Leu619Pro variant causes a new channelopathy characterised by giant cell lesions of the jaws and skull, skeletal abnormalities and polyneuropathy

Abstract

BackgroundPathogenic germline variants in Transient Receptor Potential Vanilloid 4 Cation Channel (TRPV4) lead to channelopathies, which are phenotypically diverse and heterogeneous disorders grossly divided in neuromuscular disorders and skeletal dysplasia. We recently reported in sporadic giant cell lesions of the jaws (GCLJs) novel, somatic, heterozygous, gain-of-function mutations in TRPV4, at Met713.MethodsHere we report two unrelated women with a de novo germline p.Leu619Pro TRPV4 variant and an overlapping systemic disorder affecting all organs individually described in TRPV4 channelopathies.ResultsFrom an early age, both patients had several lesions of the nervous system including progressive polyneuropathy, and multiple aggressive giant cell-rich lesions of the jaws and craniofacial/skull bones, and other skeletal lesions. One patient had a relatively milder disease phenotype possibly due to postzygotic somatic mosaicism. Indeed, the TRPV4 p.Leu619Pro variant was present at a lower frequency (variant allele frequency (VAF)=21.6%) than expected for a heterozygous variant as seen in the other proband, and showed variable regional frequency in the GCLJ (VAF ranging from 42% to 10%). In silico structural analysis suggests that the gain-of-function p.Leu619Pro alters the ion channel activity leading to constitutive ion leakage.ConclusionOur findings define a novel polysystemic syndrome due to germline TRPV4 p.Leu619Pro and further extend the spectrum of TRPV4 channelopathies. They further highlight the convergence of TRPV4 mutations on different organ systems leading to complex phenotypes which are further mitigated by possible post-zygotic mosaicism. Treatment of this disorder is challenging, and surgical intervention of the GCLJ worsens the lesions, suggesting the future use of MEK inhibitors and TRPV4 antagonists as therapeutic modalities for unmet clinical needs.

TRPV4 mutations causing mixed neuropathy and skeletal phenotypes result in severe gain of function

“…29,33,34 These abnormalities were numerous and affected the head, neck, trunk, pelvis, and extremities (Table 3). Additional notable features were spinal dysraphisms (including tethered spinal cord, which was also noted in our case) (n = 3), facial weakness (n = 2), retinopathy 32,34 (n = 3), and central sleep apnea (one prior patient and the currently reported patient). 32 Of note, two patients with the L619P mutation developed a particularly severe and unusual mixed phenotype with severe skeletal abnormalities as well as giant cell lesions of the jaw and skull, cystic lesions of the long bones and vertebrae, cervical and thoracic vertebrae fusion, and facial and skull dysmorphisms.…”

“…Additional notable features were spinal dysraphisms (including tethered spinal cord, which was also noted in our case) (n = 3), facial weakness (n = 2), retinopathy 32,34 (n = 3), and central sleep apnea (one prior patient and the currently reported patient). 32 Of note, two patients with the L619P mutation developed a particularly severe and unusual mixed phenotype with severe skeletal abnormalities as well as giant cell lesions of the jaw and skull, cystic lesions of the long bones and vertebrae, cervical and thoracic vertebrae fusion, and facial and skull dysmorphisms. 32 In our review, we did not observe definitive genotypephenotype correlation between specific TRPV4 mutations and combined neuropathy and skeletal dysplasia phenotypes, and we could not identify a pattern of neuropathic characteristics that predicted skeletal involvement.…”

“…32 Of note, two patients with the L619P mutation developed a particularly severe and unusual mixed phenotype with severe skeletal abnormalities as well as giant cell lesions of the jaw and skull, cystic lesions of the long bones and vertebrae, cervical and thoracic vertebrae fusion, and facial and skull dysmorphisms. 32 In our review, we did not observe definitive genotypephenotype correlation between specific TRPV4 mutations and combined neuropathy and skeletal dysplasia phenotypes, and we could not identify a pattern of neuropathic characteristics that predicted skeletal involvement. Skeletal disease associated with TRPV4-mediated neuropathy occurred across a range of clinical severity and mutations, consistent with prior studies highlighting the heterogeneity of TRPV4 channelopathies.…”

“…However, we identified 36 individual cases of mixed neuropathy and skeletal phenotypes arising from 19 different mutations. 10,11,[21][22][23][24][25][26][27][28][29][30][31][32][33][34] This included nine affected families as well as several individuals with de novo mutations. We analyzed these reports with respect to genotype, age of onset, neurological and skeletal manifestations, electrophysiology, and other phenotypic manifestations (Table 2).…”

Central giant cell granulomas of the jaws stromal cells harbour mutations and have osteogenic differentiation capacity, in vivo and in vitro

“…Central giant cell granulomas (CGCG) are osteolytic jaw lesions characterized by the proliferation of mononuclear and osteoclastlike giant cells in a haemorrhagic vascular background. They occur sporadically, but similar lesions may occur in genetic syndromes 1,2 or in systemic conditions. 3 CGCG may have an indolent clinical course, behaving like reactive lesions.…”