Human skeletal dysplasia caused by a constitutive activated transient receptor potential vanilloid 4 (TRPV4) cation channel mutation

Abstract

The transient receptor potential vanilloid 4 (TRPV4) cation channel, a member of the TRP vanilloid subfamily, is expressed in a broad range of tissues where it participates in the generation of Ca²⁺ signals and/or depolarization of the membrane potential. Regulation of TRPV4 abundance at the cell surface is critical for osmo- and mechanotransduction. Defects in TRPV4 are the cause of several human diseases, including brachyolmia type 3 (MIM:113500) (also known as brachyrachia or spondylometaphyseal dysplasia Kozlowski type [MIM:118452]), and metatropic dysplasia (MIM:156530) (also called metatropic dwarfism or parastremmatic dwarfism [MIM:168400]). These bone dysplasia mutants are characterized by severe dwarfism, kyphoscoliosis, distortion and bowing of the extremities, and contractures of the large joints. These diseases are characterized by a combination of decreased bone density, bowing of the long bones, platyspondyly, and striking irregularities of endochondral ossification with areas of calcific stippling and streaking in radiolucent epiphyses, metaphyses, and apophyses. In this review, we discuss the potential effect of the mutation on the regulation of TRPV4 functions, which are related to human diseases through deviated function. In particular, we emphasize how the constitutive active TRPV4 mutant affects endochondral ossification with a reduced number of hypertrophic chondrocytes and the presence of cartilage islands within the zone of primary mineralization. In addition, we summarize current knowledge about the role of TRPV4 in the pathogenesis of several diseases.

Figure 1

The TRPV4 topology and its domains. Transmembrane topology of the mouse TRPV4 (871 amino acids length). Indicated are the three ankyrin-binding repeats (ANK; as pentagon), the six trans-membrane regions (TM1-TM6), the Ca²⁺/F-actin- or microtubule-binding site (F-actin or microtubule), and the putative SGK1 phosphorylation site (S824) which is indicated by the arrow type (WT; Gene Bank #. BC127052). The putative cytoplasmic region of TRPV4 (718-871 amino acids) is also indicated by underlining.

Figure 2

The naturally mutation sites on human TRPV4. Transmembrane topology of the human TRPV4 (871 amino acids length). Indicates are the three ankyrin-binding repeats (ANK; gray bar), the six trans-membrane regions (TM1-TM6), the Ca²⁺ pore and the mutation site (WT; Gene Bank #. BC127052). The putative cytoplasmic region of N-terminal (1-471 amino acids) and C-terminal (718-871 amino acids) of TRPV4 are indicated with N and C. Two "hot spots" in TRPV4 sequences are prominent, one at the pore region and the other one in the between ANK 3 and 4 (del: deletion, delines: deletion or insertion extra sequence, fs: fame shift).

Figure 3

The scheme of proposed TRPV4 functional regulation. TRPV4 can be modulated by the putative dual (activator/inhibitor) function protein (such as F-actin or microtubule) association/dissociation from its C-terminal cytoplasmic domain (activation/inactivation) phosphorylation. After receiving a growth signal from outside, the protein kinase such as SGK1 is activated. The protein-protein interaction between TRPV4 and (F-actin or tubulin) appears to be modulated by phosphorylation on its 824 serine residue by protein kinases (right). The active TRPV4 seems to be inactivated by protein phosphatases via dephosphorylation on its Ser 824 residue (left). The inactivated TRPV4 seems to bind with tubulin (Chun et al., 2012).

Figure 4

The osteogenesis regulation mechanisms by TRPV4 signalling. TRPV4 represses alternative mesenchymal differentiation pathways such as adipocyte and chondrocyte differentiation and promote osteoblast differentiation, proliferation, and mineralization activity while blocking osteoblast apoptosis. In this review, we hope to elucidate the etiological mechanism how the mutation in TRPV4 (E797K or P799R) causes Spondylometaphyseal dysplasias Kozlowski type (SMDK) [MIM:184252], eventually. The mutant TRPV4 which is constitutively active in HEK293 cell results in the activation of osteoclast abnormally. It is unknown yet how the constitutive active TRPV4 activates osteoclast. The research hypothesis is that the constitutive active mutant TRPV4 (such as E797K, P799R) represses the chondrocyte differentiation from MSC and promotes the osteoclast activation (or the osteoblast apoptosis) with the increase of related transcription factor, such as NFATc1 (Wegierski et al., 2006). Thus, the mutant TRPV4 containing the more channel activity than the TRPV4 WT causes the abnormality of backbone morphogenesis, meanwhile the constitutive inactive mutant TRPV4 (the less channel activity than the TRPV4 WT) causes the abnormality of articular morphogenesis or the neuropathy (FDAB or HMSN2C), which is similar with that of TRPV4 (-/-) mouse (Suzuki et al., 2003b; Verma et al., 2010; Kang, 2012).

Figure 5

Hypothetical etiological role of gain-of-function TRPV4 mutant in human genetic diseases. The mutants containing the more channel activity than the TRPV4 wt lead the abnormality of backbone morphogenesis by the more Ca²⁺ influx (left). However, even though this is not completely accorded in some case yet, the mutants containing the less channel activity causes the abnormality of articular morphogenesis or the neuropathy by the less Ca²⁺ influx (right). Because both SMA/HMSN2C and CMT2C are caused by G806A (exon 5) mutation, presently, it is unclear whether the channel activity of mutant TRPV4 R269H is increased than that of TRPV4 WT.