TRPV4 related skeletal dysplasias: a phenotypic spectrum highlighted byclinical, radiographic, and molecular studies in 21 new families

Andreucci, Elena; Aftimos, Salim; Alcausin, Melanie; Haan, Eric; Hunter, Warwick; Kannu, Peter; Kerr, Bronwyn; McGillivray, George; Gardner, R. J McKinlay; Patricelli, Maria Grazia; Sillence, David; Thompson, Elizabeth; Zacharin, Margaret; Zankl, Andreas; Lamandé, Shireen R.; Savarirayan, Ravi

doi:10.1186/1750-1172-6-37

Cited by 50 publications

(43 citation statements)

References 21 publications

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“…Es expresado de manera amplia y participa en diversos procesos fisiológicos a través de la respuesta a diferentes estímulos. 1,7 Las funciones de esta proteína compleja siguen siendo desconocidas. No obstante, el hecho de que las mutaciones en el gen TRPV4 causan displasias óseas es consistente con que el canal se expresa en los osteoblastos y osteoclastos.…”

Section: Discussionunclassified

“…1 Se caracteriza por presentar dismorfias craneofaciales, que incluyen prominencia frontal e hipoplasia medio facial, tronco corto con cifoescoliosis progresiva, platispondilia grave, retraso en la osificación de los huesos isquion y pubis, acortamiento de huesos largos con diáfisis y metáfisis anchas. [1][2][3][4] Entre las principales complicaciones, se describen la compresión de la médula espinal cervical, que puede afectar el desarrollo motor, y el empeoramiento de la cifoescoliosis. Es causada por mutación en el gen TRPV4, que se localiza en 12q24.11.…”

Section: Introductionunclassified

“…Presenta un patrón de herencia autosómica dominante, en ocasiones con fenotipo grave (letal). 1,5,6 Camacho et al 2 demostraron que mutaciones en el gen TRPV4 eran causantes de la entidad. Las características clave del diagnóstico están bien descritas con más de 75 casos informados.…”

Section: Introductionunclassified

“…Estos datos sugieren que la diferenciación de los condrocitos alterados en la placa de crecimiento conducen a los hallazgos clínicos de la DM. 1,2,13 Se presentó un nuevo caso de DM no letal, cuyo diagnóstico se realizó a través de los hallazgos clínicos y radiológicos. Este fue corroborado por estudio molecular, que informó una mutación de tipo deleción en heterocigosis en el exón 11 no informada previamente en el gen TRPV4.…”

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Displasia metatrópica en una niña con mutación c.1811_1812delinsAT en el exón 11 del gen TRPV4 no informada previamente

et al. 2015

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Presentación de casos clínicos RESUMENLa displasia metatrópica es una alteración esquelética con heterogeneidad clínica, caracterizada por dismorfias craneofaciales, que incluyen prominencia frontal e hipoplasia medio facial, tronco corto con cifoescoliosis progresiva y acortamiento de las extremidades. El gen TRPV4 se localiza en 12q24.11; codifica a un canal de catión con permeabilidad no selectiva al calcio, el cual se expresa y participa en muchos procesos fisiológicos en respuesta a diversos estímulos. Más de 50 mutaciones en TRPV4 han sido descritas. Se presenta el caso de una niña de 7 meses de edad con mutación heterocigota c.1811_1812delinsAT; p.I604N en el intrón 11 no informada previamente en el gen TRPV4 y con hallazgos clínicos compatibles con displasia metatrópica. Palabras clave: displasia metatrópica, TRPV4, c.1811_1812delinsAT. ABSTRACTMetatropic dysplasia is a skeletal disorder with clinical heterogeneity, characterized by craniofacial dysmorphy including frontal bossing and midface hypoplasia, short trunk, progressive kyphoscoliosis and shortened limbs. The TRPV4 gene is located on 12q24.11, coding a cation channel with nonselective permeability to calcium; it is expressed and involved in many physiological processes through responses to different stimuli. Over 50 mutations in TRPV4 have been described. We present a seven months old girl with heterozygous mutation c.1811_1812delinsAT; p.I604N in intron 11 not previously reported in the TRPV4 gene and with clinical findings compatible with metatropic dysplasia.

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Section: Introductionunclassified

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Displasia metatrópica en una niña con mutación c.1811_1812delinsAT en el exón 11 del gen TRPV4 no informada previamente

et al. 2015

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“…Mutations in TRPV4 have also been identified in other skeletal disorders: digital arthropathy-brachydactyly (MIM: 606835); [Lamande et al 2011], brachyolmia type 3 (MIM: 113500); [Rock et al, 2008], Maroteaux type of spondyloepiphyseal dysplasia (MIM: 184095); [Nishimura et al, 2010], parastremmatic dwarfism (MIM: 168400); [Nishimura et al, 2010], and in lethal and nonlethal autosomal dominant metatropic dysplasias (MIM:156530); [Krakow et al, 2009; Camacho et al, 2010]. These six skeletal disorders form an overlapping phenotypic spectrum of increasing severity, from mild digital arthropathy-brachydactyly to more severe forms, with metatropic dysplasia at the end of the scale [Andreucci et al, 2011; Nemec et al, 2012; Nilius and Voets, 2013]. …”

Section: Introductionmentioning

confidence: 99%

SMD Kozlowski type caused by p.Arg594His substitution in TRPV4 reveals abnormal ossification and notochordal remnants in discs and vertebrae

Biegański

Beighton

Łukaszewski

et al. 2017

European Journal of Medical Genetics

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Spondylometaphyseal dysplasia Kozlowski type (SMDK) is a monogenic disorder within the TRPV4 dysplasia spectrum and has characteristic spinal and metaphyseal involvement. We report skeletal MR imaging in a two-year-old patient who manifested typical clinical and radiographic features of SMDK. The diagnosis was confirmed by molecular analysis which revealed a mutation NM_021625.4:c.1781G>A - p.(Arg594His) in exon 11 of the TRPV4 gene. We have documented abnormalities in endochondral formation of the long and short tubular bones as well as round bones of the wrists and feet. The vertebral bodies had increased thickness of hyaline cartilage which enveloped ossification centers. The vertebrae and discs also had abnormalities in size, shape and structure. These anomalies were most likely the consequence of notochordal remnants presence within the intervertebral discs and in the vertebral bodies. The advantages of MR imaging in bone dysplasias caused by TRPV4 mutations are emphasized in this article.

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

Taga

Peyton

Goretzki

et al. 2022

Ann Clin Transl Neurol

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Objective: Distinct dominant mutations in the calcium-permeable ion channel TRPV4 (transient receptor potential vanilloid 4) typically cause nonoverlapping diseases of either the neuromuscular or skeletal systems. However, accumulating evidence suggests that some patients develop mixed phenotypes that include elements of both neuromuscular and skeletal disease. We sought to define the genetic and clinical features of these patients. Methods: We report a 2-year-old with a novel R616G mutation in TRPV4 with a severe neuropathy phenotype and bilateral vocal cord paralysis. Interestingly, a different substitution at the same residue, R616Q, has been reported in families with isolated skeletal dysplasia. To gain insight into clinical features and potential genetic determinants of mixed phenotypes, we perform in-depth analysis of previously reported patients along with functional and structural assessment of selected mutations. Results: We describe a wide range of neuromuscular and skeletal manifestations and highlight specific mutations that are more frequently associated with overlap syndromes. We find that mutations causing severe, mixed phenotypes have an earlier age of onset and result in more marked elevations of intracellular calcium, increased cytotoxicity, and reduced sensitivity to TRPV4 antagonism. Structural analysis of the two mutations with the most dramatic gain of ion channel function suggests that these mutants likely cause constitutive channel opening through disruption of the TRPV4 S5 transmembrane domain. Interpretation: These findings demonstrate that the degree of baseline calcium elevation correlates with development of mixed phenotypes and sensitivity to pharmacologic channel inhibition, observations that will be critical for the design of future clinical trials for TRPV4 channelopathies.

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TRPV4 related skeletal dysplasias: a phenotypic spectrum highlighted byclinical, radiographic, and molecular studies in 21 new families

Cited by 50 publications

References 21 publications

Displasia metatrópica en una niña con mutación c.1811_1812delinsAT en el exón 11 del gen TRPV4 no informada previamente

Displasia metatrópica en una niña con mutación c.1811_1812delinsAT en el exón 11 del gen TRPV4 no informada previamente

SMD Kozlowski type caused by p.Arg594His substitution in TRPV4 reveals abnormal ossification and notochordal remnants in discs and vertebrae

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

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