Homozygous TRPV4 mutation causes congenital distal spinal muscular atrophy and arthrogryposis

Abstract

ObjectiveTo identify the genetic cause of disease in a form of congenital spinal muscular atrophy and arthrogryposis (CSMAA).MethodsA 2-year-old boy was diagnosed with arthrogryposis multiplex congenita, severe skeletal abnormalities, torticollis, vocal cord paralysis, and diminished lower limb movement. Whole-exome sequencing (WES) was performed on the proband and family members. In silico modeling of protein structure and heterologous protein expression and cytotoxicity assays were performed to validate pathogenicity of the identified variant.ResultsWES revealed a homozygous mutation in the TRPV4 gene (c.281C>T; p.S94L). The identification of a recessive mutation in TRPV4 extends the spectrum of mutations in recessive forms of the TRPV4-associated disease. p.S94L and other previously identified TRPV4 variants in different protein domains were compared in structural modeling and functional studies. In silico structural modeling suggests that the p.S94L mutation is in the disordered N-terminal region proximal to important regulatory binding sites for phosphoinositides and for PACSIN3, which could lead to alterations in trafficking and/or channel sensitivity. Functional studies by Western blot and immunohistochemical analysis show that p.S94L increased TRPV4 activity-based cytotoxicity and resultant decreased TRPV4 expression levels, therefore involves a gain-of-function mechanism.ConclusionsThis study identifies a novel homozygous mutation in TRPV4 as a cause of the recessive form of CSMAA.

TRPing to the Point of Clarity: Understanding the Function of the Complex TRPV4 Ion Channel

“…Mutations in TRPV4 lead to a variety of conditions including different types of skeletal dysplasia (affected bone growth), brachydactyly (shortness of fingers and toes), familial digital arthropathy brachydactyly (FDAB), a progressive osteoarthropathy [ 123 , 124 ], as well as neuropathies including sensory and motor defects [ 125 ]. TRPV4-related diseases generally demonstrate autosomal dominant inheritance, but some disease-causing mutations have incomplete and variable disease penetration [ 126 ]. Curiously, and in line with the mild phenotype of the trpv4 -/- mice, the majority of the disease-causing mutant TRPV4 ion channels are reported as gain-of-function mutations, which lead to higher basal and evoked whole-cell Ca 2+ currents in heterologous expression systems [ 6 , 127 ].…”

“…Some TRPV4 mutations cause degeneration of motor and sensory neurons [ 125 , 139 ], and generally encompass disturbances in distal limb function, vocal cord paresis, hearing defects and/or bladder hyperactivity [ 125 , 139 , 140 , 141 , 142 , 143 ]. Congenital distal spinal motor neuropathy (CDSMA) is caused by N-terminal mutations (see Table 2 and Figure 3 for an overview of disease-causing mutations), and it is characterized by a motor neuron deficiency leading to muscle atrophy in the lower part of the body [ 126 ]. Scapuloperoneal spinal muscular atrophy (SPSMA) is predominantly caused by N-terminal mutations ( Table 2 ) [ 144 ].…”

TRP channels in health and disease at a glance

“…Mutations in TRPV4 have been identified in patients with various neurodegenerative disorders, such as Charcot-Marie-Tooth disease type 2C (CMT2C), scapuloperoneal spinal muscular atrophy (SPSMA), distal spinal motor neuropathy, distal spinal muscular atrophy (SMA) (Auer-Grumbach et al, 2010;Deng et al, 2010;Fiorillo et al, 2012;Lamande et al, 2011;Landoure et al, 2010), and severe intellectual disability and neuropathy (Thibodeau et al, 2017). Mutations in TRPV4 also cause other disorders, including various skeletal dysplasias, ranging from mild autosomal dominant brachyolmia to severe metatropic dysplasia (MD) (Nilius and Voets, 2013;Toft-Bertelsen and MacAulay, 2021), arthropathy (Lamande et al, 2011;McNulty et al, 2015), arthrogryposis (Velilla et al, 2019) and progressive osteoarthropathy (Lamande et al, 2011;Nishimura et al, 2012). The majority of these disease-causing TRPM4 mutations are GOF mutations (Nilius and Voets, 2013), whereas some are LOF mutations (Lamande et al, 2011).…”

Revisiting the complex architecture of ALS in Turkey: Expanding genotypes, shared phenotypes, molecular networks, and a public variant database

“…Venn diagram is drawn according to the disease-gene associations obtained from the literature (Akçimen et al, 2019;Al-Saif, Al-Mohanna, & Bohlega, 2011;Annesi et al, 2005;Brenner et al, 2018;Chen et al, 2004;Cirulli et al, 2015;Cottenie et al, 2014;Daoud et al, 2012;Deschauer et al, 2012;Frasquet, Va, & Sevilla, 2017;Greenway et al, 2006;Grohmann et al, 2001;Hermosura et al, 2005;Hughes et al, 2001;Ishiura et al, 2012;Iskender et al, 2015;Kimonis, Fulchiero, Vesa, & Watts, 2008;Maruyama et al, 2010;Maystadt et al, 2007;Nalini, Pandraud, Mok, & Houlden, 2013;H. P. Nguyen, Van Broeckhoven, & van der Zee, 2018;Stoll et al, 2016;Sumner et al, 2013;Synofzik et al, 2016;Takahashi et al, 2013;Tunca et al, 2018;Velilla et al, 2019;Yang et al, 2001). ALS, amyotrophic lateral sclerosis; AO, age of onset e22 | (Fogel et al, 2014;Fogel, Satya-Murti, & Cohen, 2016;Trujillano et al, 2017).…”