Novel and recurrent TRPV4 mutations and their association with distinct phenotypes within the TRPV4 dysplasia family

J. Dai, O. H. Kim, T. J. Cho, M. Schmidt-Rimpler, H. Tonoki, K. Takikawa, N. Haga, K. Miyoshi, H. Kitoh, W. J. Yoo, I. H. Choi, Hae Ryong Song, D. K. Jin, H. T. Kim, H. Kamasaki, P. Bianchi, G. Grigelioniene, S. Nampoothiri, M. Minagawa, S. I. MiyagawaT. Fukao, C. Marcelis, M. C E Jansweijer, R. C M Hennekam, F. Bedeschi, A. Mustonen, Q. Jiang, H. Ohashi, T. Furuichi, S. Unger, B. Zabel, E. Lausch, A. Superti-Furga, G. Nishimura, Shiro Ikegawa

Research output: Contribution to journalArticle

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Abstract

Background: Mutations in TRPV4, a gene that encodes a Ca2+ permeable non-selective cation channel, have recently been found in a spectrum of skeletal dysplasias that includes brachyolmia, spondylometaphyseal dysplasia, Kozlowski type (SMDK) and metatropic dysplasia (MD). Only a total of seven missense mutations were detected, however. The full spectrum of TRPV4 mutations and their phenotypes remained unclear. Objectives and methods: To examine TRPV4 mutation spectrum and phenotype-genotype association, we searched for TRPV4 mutations by PCR-direct sequencing from genomic DNA in 22 MD and 20 SMDK probands. Results: TRPV4 mutations were found in all but one MD subject. In total, 19 different heterozygous mutations were identified in 41 subjects; two were recurrent and 17 were novel. In MD, a recurrent P799L mutation was identified in nine subjects, as well as 10 novel mutations including F471del, the first deletion mutation of TRPV4. In SMDK, a recurrent R594H mutation was identified in 12 subjects and seven novel mutations. An association between the position of mutations and the disease phenotype was also observed. Thus, P799 in exon 15 is a hot codon for MD mutations, as four different amino acid substitutions have been observed at this codon; while R594 in exon 11 is a hotspot for SMDK mutations. Conclusion: The TRPV4 mutation spectrum in MD and SMDK, which showed genotype-phenotype correlation and potential functional significance of mutations that are non-randomly distributed over the gene, was presented in this study. The results would help diagnostic laboratories establish efficient screening strategies for genetic diagnosis of the TRPV4 dysplasia family diseases.

Original languageEnglish
Pages (from-to)704-709
Number of pages6
JournalJournal of Medical Genetics
Volume47
Issue number10
DOIs
Publication statusPublished - 2010 Oct 1

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Phenotype
Mutation
Genetic Association Studies
Codon
Exons
Sequence Deletion
Genetic Testing
Missense Mutation
Amino Acid Substitution
DNA Sequence Analysis
Genes
Metatropic dwarfism
Cations
Kozlowski type Spondylometaphyseal dysplasia
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Dai, J., Kim, O. H., Cho, T. J., Schmidt-Rimpler, M., Tonoki, H., Takikawa, K., ... Ikegawa, S. (2010). Novel and recurrent TRPV4 mutations and their association with distinct phenotypes within the TRPV4 dysplasia family. Journal of Medical Genetics, 47(10), 704-709. https://doi.org/10.1136/jmg.2009.075358

Novel and recurrent TRPV4 mutations and their association with distinct phenotypes within the TRPV4 dysplasia family. / Dai, J.; Kim, O. H.; Cho, T. J.; Schmidt-Rimpler, M.; Tonoki, H.; Takikawa, K.; Haga, N.; Miyoshi, K.; Kitoh, H.; Yoo, W. J.; Choi, I. H.; Song, Hae Ryong; Jin, D. K.; Kim, H. T.; Kamasaki, H.; Bianchi, P.; Grigelioniene, G.; Nampoothiri, S.; Minagawa, M.; Miyagawa, S. I.; Fukao, T.; Marcelis, C.; Jansweijer, M. C E; Hennekam, R. C M; Bedeschi, F.; Mustonen, A.; Jiang, Q.; Ohashi, H.; Furuichi, T.; Unger, S.; Zabel, B.; Lausch, E.; Superti-Furga, A.; Nishimura, G.; Ikegawa, Shiro.

In: Journal of Medical Genetics, Vol. 47, No. 10, 01.10.2010, p. 704-709.

Research output: Contribution to journalArticle

Dai, J, Kim, OH, Cho, TJ, Schmidt-Rimpler, M, Tonoki, H, Takikawa, K, Haga, N, Miyoshi, K, Kitoh, H, Yoo, WJ, Choi, IH, Song, HR, Jin, DK, Kim, HT, Kamasaki, H, Bianchi, P, Grigelioniene, G, Nampoothiri, S, Minagawa, M, Miyagawa, SI, Fukao, T, Marcelis, C, Jansweijer, MCE, Hennekam, RCM, Bedeschi, F, Mustonen, A, Jiang, Q, Ohashi, H, Furuichi, T, Unger, S, Zabel, B, Lausch, E, Superti-Furga, A, Nishimura, G & Ikegawa, S 2010, 'Novel and recurrent TRPV4 mutations and their association with distinct phenotypes within the TRPV4 dysplasia family', Journal of Medical Genetics, vol. 47, no. 10, pp. 704-709. https://doi.org/10.1136/jmg.2009.075358
Dai, J. ; Kim, O. H. ; Cho, T. J. ; Schmidt-Rimpler, M. ; Tonoki, H. ; Takikawa, K. ; Haga, N. ; Miyoshi, K. ; Kitoh, H. ; Yoo, W. J. ; Choi, I. H. ; Song, Hae Ryong ; Jin, D. K. ; Kim, H. T. ; Kamasaki, H. ; Bianchi, P. ; Grigelioniene, G. ; Nampoothiri, S. ; Minagawa, M. ; Miyagawa, S. I. ; Fukao, T. ; Marcelis, C. ; Jansweijer, M. C E ; Hennekam, R. C M ; Bedeschi, F. ; Mustonen, A. ; Jiang, Q. ; Ohashi, H. ; Furuichi, T. ; Unger, S. ; Zabel, B. ; Lausch, E. ; Superti-Furga, A. ; Nishimura, G. ; Ikegawa, Shiro. / Novel and recurrent TRPV4 mutations and their association with distinct phenotypes within the TRPV4 dysplasia family. In: Journal of Medical Genetics. 2010 ; Vol. 47, No. 10. pp. 704-709.
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abstract = "Background: Mutations in TRPV4, a gene that encodes a Ca2+ permeable non-selective cation channel, have recently been found in a spectrum of skeletal dysplasias that includes brachyolmia, spondylometaphyseal dysplasia, Kozlowski type (SMDK) and metatropic dysplasia (MD). Only a total of seven missense mutations were detected, however. The full spectrum of TRPV4 mutations and their phenotypes remained unclear. Objectives and methods: To examine TRPV4 mutation spectrum and phenotype-genotype association, we searched for TRPV4 mutations by PCR-direct sequencing from genomic DNA in 22 MD and 20 SMDK probands. Results: TRPV4 mutations were found in all but one MD subject. In total, 19 different heterozygous mutations were identified in 41 subjects; two were recurrent and 17 were novel. In MD, a recurrent P799L mutation was identified in nine subjects, as well as 10 novel mutations including F471del, the first deletion mutation of TRPV4. In SMDK, a recurrent R594H mutation was identified in 12 subjects and seven novel mutations. An association between the position of mutations and the disease phenotype was also observed. Thus, P799 in exon 15 is a hot codon for MD mutations, as four different amino acid substitutions have been observed at this codon; while R594 in exon 11 is a hotspot for SMDK mutations. Conclusion: The TRPV4 mutation spectrum in MD and SMDK, which showed genotype-phenotype correlation and potential functional significance of mutations that are non-randomly distributed over the gene, was presented in this study. The results would help diagnostic laboratories establish efficient screening strategies for genetic diagnosis of the TRPV4 dysplasia family diseases.",
author = "J. Dai and Kim, {O. H.} and Cho, {T. J.} and M. Schmidt-Rimpler and H. Tonoki and K. Takikawa and N. Haga and K. Miyoshi and H. Kitoh and Yoo, {W. J.} and Choi, {I. H.} and Song, {Hae Ryong} and Jin, {D. K.} and Kim, {H. T.} and H. Kamasaki and P. Bianchi and G. Grigelioniene and S. Nampoothiri and M. Minagawa and Miyagawa, {S. I.} and T. Fukao and C. Marcelis and Jansweijer, {M. C E} and Hennekam, {R. C M} and F. Bedeschi and A. Mustonen and Q. Jiang and H. Ohashi and T. Furuichi and S. Unger and B. Zabel and E. Lausch and A. Superti-Furga and G. Nishimura and Shiro Ikegawa",
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T1 - Novel and recurrent TRPV4 mutations and their association with distinct phenotypes within the TRPV4 dysplasia family

AU - Dai, J.

AU - Kim, O. H.

AU - Cho, T. J.

AU - Schmidt-Rimpler, M.

AU - Tonoki, H.

AU - Takikawa, K.

AU - Haga, N.

AU - Miyoshi, K.

AU - Kitoh, H.

AU - Yoo, W. J.

AU - Choi, I. H.

AU - Song, Hae Ryong

AU - Jin, D. K.

AU - Kim, H. T.

AU - Kamasaki, H.

AU - Bianchi, P.

AU - Grigelioniene, G.

AU - Nampoothiri, S.

AU - Minagawa, M.

AU - Miyagawa, S. I.

AU - Fukao, T.

AU - Marcelis, C.

AU - Jansweijer, M. C E

AU - Hennekam, R. C M

AU - Bedeschi, F.

AU - Mustonen, A.

AU - Jiang, Q.

AU - Ohashi, H.

AU - Furuichi, T.

AU - Unger, S.

AU - Zabel, B.

AU - Lausch, E.

AU - Superti-Furga, A.

AU - Nishimura, G.

AU - Ikegawa, Shiro

PY - 2010/10/1

Y1 - 2010/10/1

N2 - Background: Mutations in TRPV4, a gene that encodes a Ca2+ permeable non-selective cation channel, have recently been found in a spectrum of skeletal dysplasias that includes brachyolmia, spondylometaphyseal dysplasia, Kozlowski type (SMDK) and metatropic dysplasia (MD). Only a total of seven missense mutations were detected, however. The full spectrum of TRPV4 mutations and their phenotypes remained unclear. Objectives and methods: To examine TRPV4 mutation spectrum and phenotype-genotype association, we searched for TRPV4 mutations by PCR-direct sequencing from genomic DNA in 22 MD and 20 SMDK probands. Results: TRPV4 mutations were found in all but one MD subject. In total, 19 different heterozygous mutations were identified in 41 subjects; two were recurrent and 17 were novel. In MD, a recurrent P799L mutation was identified in nine subjects, as well as 10 novel mutations including F471del, the first deletion mutation of TRPV4. In SMDK, a recurrent R594H mutation was identified in 12 subjects and seven novel mutations. An association between the position of mutations and the disease phenotype was also observed. Thus, P799 in exon 15 is a hot codon for MD mutations, as four different amino acid substitutions have been observed at this codon; while R594 in exon 11 is a hotspot for SMDK mutations. Conclusion: The TRPV4 mutation spectrum in MD and SMDK, which showed genotype-phenotype correlation and potential functional significance of mutations that are non-randomly distributed over the gene, was presented in this study. The results would help diagnostic laboratories establish efficient screening strategies for genetic diagnosis of the TRPV4 dysplasia family diseases.

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