Bi-allelic loss of function variants of TBX6 causes a spectrum of malformation of spine and rib including congenital scoliosis and spondylocostal dysostosis

Nao Otomo, Kazuki Takeda, Shunsuke Kawai, Ikuyo Kou, Long Guo, Mitsujiro Osawa, Cantas Alev, Noriaki Kawakami, Noriko Miyake, Naomichi Matsumoto, Yukuto Yasuhiko, Toshiaki Kotani, Teppei Suzuki, Koki Uno, Hideki Sudo, Satoshi Inami, Hiroshi Taneichi, Hideki Shigematsu, Kei Watanabe, Ikuho YonezawaRyo Sugawara, Yuki Taniguchi, Shohei Minami, Kazuo Kaneko, Masaya Nakamura, Morio Matsumoto, Junya Toguchida, Koota Watanabe, Shiro Ikegawa

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Abstract

Background: Congenital scoliosis (CS) is a common vertebral malformation. Spondylocostal dysostosis (SCD) is a rare skeletal dysplasia characterised by multiple vertebral malformations and rib anomalies. In a previous study, a compound heterozygosity for a null mutation and a risk haplotype composed by three single-nucleotide polymorphisms in TBX6 have been reported as a disease-causing model of CS. Another study identified bi-allelic missense variants in a SCD patient. The purpose of our study is to identify TBX6 variants in CS and SCD and examine their pathogenicity. Methods: We recruited 200 patients with CS or SCD and investigated TBX6 variants. We evaluated the pathogenicity of the variants by in silico prediction and in vitro experiments. Results: We identified five 16p11.2 deletions, one splice-site variant and five missense variants in 10 patients. In vitro functional assays for missense variants identified in the previous and present studies demonstrated that most of the variants caused abnormal localisation of TBX6 proteins. We confirmed mislocalisation of TBX6 proteins in presomitic mesoderm cells induced from SCD patient-derived iPS cells. In induced cells, we found decreased mRNA expressions of TBX6 and its downstream genes were involved in somite formation. All CS patients with missense variants had the risk haplotype in the opposite allele, while a SCD patient with bi-allelic missense variants did not have the haplotype. Conclusions: Our study suggests that bi-allelic loss of function variants of TBX6 cause a spectrum of phenotypes including CS and SCD, depending on the severity of the loss of TBX6 function.

Original languageEnglish
JournalJournal of medical genetics
DOIs
Publication statusPublished - 2019 Jan 1

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Loss of Heterozygosity
Scoliosis
Ribs
Spine
Haplotypes
Virulence
Somites
Mesoderm
Jarcho-Levin syndrome
Computer Simulation
Single Nucleotide Polymorphism
Proteins
Alleles
Phenotype
Messenger RNA
Mutation
Genes

Keywords

  • bi-allelic mutation
  • congenital scoliosis
  • mislocalisation
  • spondylocostal dysostosis
  • TBX6

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Bi-allelic loss of function variants of TBX6 causes a spectrum of malformation of spine and rib including congenital scoliosis and spondylocostal dysostosis. / Otomo, Nao; Takeda, Kazuki; Kawai, Shunsuke; Kou, Ikuyo; Guo, Long; Osawa, Mitsujiro; Alev, Cantas; Kawakami, Noriaki; Miyake, Noriko; Matsumoto, Naomichi; Yasuhiko, Yukuto; Kotani, Toshiaki; Suzuki, Teppei; Uno, Koki; Sudo, Hideki; Inami, Satoshi; Taneichi, Hiroshi; Shigematsu, Hideki; Watanabe, Kei; Yonezawa, Ikuho; Sugawara, Ryo; Taniguchi, Yuki; Minami, Shohei; Kaneko, Kazuo; Nakamura, Masaya; Matsumoto, Morio; Toguchida, Junya; Watanabe, Koota; Ikegawa, Shiro.

In: Journal of medical genetics, 01.01.2019.

Research output: Contribution to journalArticle

Otomo, N, Takeda, K, Kawai, S, Kou, I, Guo, L, Osawa, M, Alev, C, Kawakami, N, Miyake, N, Matsumoto, N, Yasuhiko, Y, Kotani, T, Suzuki, T, Uno, K, Sudo, H, Inami, S, Taneichi, H, Shigematsu, H, Watanabe, K, Yonezawa, I, Sugawara, R, Taniguchi, Y, Minami, S, Kaneko, K, Nakamura, M, Matsumoto, M, Toguchida, J, Watanabe, K & Ikegawa, S 2019, 'Bi-allelic loss of function variants of TBX6 causes a spectrum of malformation of spine and rib including congenital scoliosis and spondylocostal dysostosis', Journal of medical genetics. https://doi.org/10.1136/jmedgenet-2018-105920
Otomo, Nao ; Takeda, Kazuki ; Kawai, Shunsuke ; Kou, Ikuyo ; Guo, Long ; Osawa, Mitsujiro ; Alev, Cantas ; Kawakami, Noriaki ; Miyake, Noriko ; Matsumoto, Naomichi ; Yasuhiko, Yukuto ; Kotani, Toshiaki ; Suzuki, Teppei ; Uno, Koki ; Sudo, Hideki ; Inami, Satoshi ; Taneichi, Hiroshi ; Shigematsu, Hideki ; Watanabe, Kei ; Yonezawa, Ikuho ; Sugawara, Ryo ; Taniguchi, Yuki ; Minami, Shohei ; Kaneko, Kazuo ; Nakamura, Masaya ; Matsumoto, Morio ; Toguchida, Junya ; Watanabe, Koota ; Ikegawa, Shiro. / Bi-allelic loss of function variants of TBX6 causes a spectrum of malformation of spine and rib including congenital scoliosis and spondylocostal dysostosis. In: Journal of medical genetics. 2019.
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abstract = "Background: Congenital scoliosis (CS) is a common vertebral malformation. Spondylocostal dysostosis (SCD) is a rare skeletal dysplasia characterised by multiple vertebral malformations and rib anomalies. In a previous study, a compound heterozygosity for a null mutation and a risk haplotype composed by three single-nucleotide polymorphisms in TBX6 have been reported as a disease-causing model of CS. Another study identified bi-allelic missense variants in a SCD patient. The purpose of our study is to identify TBX6 variants in CS and SCD and examine their pathogenicity. Methods: We recruited 200 patients with CS or SCD and investigated TBX6 variants. We evaluated the pathogenicity of the variants by in silico prediction and in vitro experiments. Results: We identified five 16p11.2 deletions, one splice-site variant and five missense variants in 10 patients. In vitro functional assays for missense variants identified in the previous and present studies demonstrated that most of the variants caused abnormal localisation of TBX6 proteins. We confirmed mislocalisation of TBX6 proteins in presomitic mesoderm cells induced from SCD patient-derived iPS cells. In induced cells, we found decreased mRNA expressions of TBX6 and its downstream genes were involved in somite formation. All CS patients with missense variants had the risk haplotype in the opposite allele, while a SCD patient with bi-allelic missense variants did not have the haplotype. Conclusions: Our study suggests that bi-allelic loss of function variants of TBX6 cause a spectrum of phenotypes including CS and SCD, depending on the severity of the loss of TBX6 function.",
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TY - JOUR

T1 - Bi-allelic loss of function variants of TBX6 causes a spectrum of malformation of spine and rib including congenital scoliosis and spondylocostal dysostosis

AU - Otomo, Nao

AU - Takeda, Kazuki

AU - Kawai, Shunsuke

AU - Kou, Ikuyo

AU - Guo, Long

AU - Osawa, Mitsujiro

AU - Alev, Cantas

AU - Kawakami, Noriaki

AU - Miyake, Noriko

AU - Matsumoto, Naomichi

AU - Yasuhiko, Yukuto

AU - Kotani, Toshiaki

AU - Suzuki, Teppei

AU - Uno, Koki

AU - Sudo, Hideki

AU - Inami, Satoshi

AU - Taneichi, Hiroshi

AU - Shigematsu, Hideki

AU - Watanabe, Kei

AU - Yonezawa, Ikuho

AU - Sugawara, Ryo

AU - Taniguchi, Yuki

AU - Minami, Shohei

AU - Kaneko, Kazuo

AU - Nakamura, Masaya

AU - Matsumoto, Morio

AU - Toguchida, Junya

AU - Watanabe, Koota

AU - Ikegawa, Shiro

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Background: Congenital scoliosis (CS) is a common vertebral malformation. Spondylocostal dysostosis (SCD) is a rare skeletal dysplasia characterised by multiple vertebral malformations and rib anomalies. In a previous study, a compound heterozygosity for a null mutation and a risk haplotype composed by three single-nucleotide polymorphisms in TBX6 have been reported as a disease-causing model of CS. Another study identified bi-allelic missense variants in a SCD patient. The purpose of our study is to identify TBX6 variants in CS and SCD and examine their pathogenicity. Methods: We recruited 200 patients with CS or SCD and investigated TBX6 variants. We evaluated the pathogenicity of the variants by in silico prediction and in vitro experiments. Results: We identified five 16p11.2 deletions, one splice-site variant and five missense variants in 10 patients. In vitro functional assays for missense variants identified in the previous and present studies demonstrated that most of the variants caused abnormal localisation of TBX6 proteins. We confirmed mislocalisation of TBX6 proteins in presomitic mesoderm cells induced from SCD patient-derived iPS cells. In induced cells, we found decreased mRNA expressions of TBX6 and its downstream genes were involved in somite formation. All CS patients with missense variants had the risk haplotype in the opposite allele, while a SCD patient with bi-allelic missense variants did not have the haplotype. Conclusions: Our study suggests that bi-allelic loss of function variants of TBX6 cause a spectrum of phenotypes including CS and SCD, depending on the severity of the loss of TBX6 function.

AB - Background: Congenital scoliosis (CS) is a common vertebral malformation. Spondylocostal dysostosis (SCD) is a rare skeletal dysplasia characterised by multiple vertebral malformations and rib anomalies. In a previous study, a compound heterozygosity for a null mutation and a risk haplotype composed by three single-nucleotide polymorphisms in TBX6 have been reported as a disease-causing model of CS. Another study identified bi-allelic missense variants in a SCD patient. The purpose of our study is to identify TBX6 variants in CS and SCD and examine their pathogenicity. Methods: We recruited 200 patients with CS or SCD and investigated TBX6 variants. We evaluated the pathogenicity of the variants by in silico prediction and in vitro experiments. Results: We identified five 16p11.2 deletions, one splice-site variant and five missense variants in 10 patients. In vitro functional assays for missense variants identified in the previous and present studies demonstrated that most of the variants caused abnormal localisation of TBX6 proteins. We confirmed mislocalisation of TBX6 proteins in presomitic mesoderm cells induced from SCD patient-derived iPS cells. In induced cells, we found decreased mRNA expressions of TBX6 and its downstream genes were involved in somite formation. All CS patients with missense variants had the risk haplotype in the opposite allele, while a SCD patient with bi-allelic missense variants did not have the haplotype. Conclusions: Our study suggests that bi-allelic loss of function variants of TBX6 cause a spectrum of phenotypes including CS and SCD, depending on the severity of the loss of TBX6 function.

KW - bi-allelic mutation

KW - congenital scoliosis

KW - mislocalisation

KW - spondylocostal dysostosis

KW - TBX6

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U2 - 10.1136/jmedgenet-2018-105920

DO - 10.1136/jmedgenet-2018-105920

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JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

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