title: Compound Heterozygosity for Null Mutations and a Common Hypomorphic Risk Haplotype in TBX6 Causes Congenital Scoliosis.
abstract: Congenital scoliosis (CS) occurs as a result of vertebral malformations and has an incidence of 0.5-1/1,000 births. Recently, TBX6 on chromosome 16p11.2 was reported as a disease gene for CS; about 10% of Chinese CS patients were compound heterozygotes for rare null mutations and a common haplotype defined by three SNPs in TBX6. All patients had hemivertebrae. We recruited 94 Japanese CS patients, investigated the TBX6 locus for both mutations and the risk haplotype, examined transcriptional activities of mutant TBX6 in vitro, and evaluated clinical and radiographic features. We identified TBX6 null mutations in nine patients, including a missense mutation that had a loss of function in vitro. All had the risk haplotype in the opposite allele. One of the mutations showed dominant negative effect. Although all Chinese patients had one or more hemivertebrae, two Japanese patients did not have hemivertebra. The compound heterozygosity of null mutations and the common risk haplotype in TBX6 also causes CS in Japanese patients with similar incidence. Hemivertebra was not a specific type of spinal malformation in TBX6-associated CS (TACS). A heterozygous TBX6 loss-of-function mutation has been reported in a family with autosomal-dominant spondylocostal dysostosis, but it may represent a spectrum of the same disease with TACS.
authors.affiliation: Laboratory of Bone and Joint Diseases, Center for Integrative Medical Sciences, RIKEN, Tokyo, 160-8582, Japan.|Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, 108-8639, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Takeda
authors.affiliation: Laboratory of Bone and Joint Diseases, Center for Integrative Medical Sciences, RIKEN, Tokyo, 160-8582, Japan.
authors.forename: Ikuyo
authors.initials: I
authors.lastname: Kou
authors.affiliation: Department of Orthopaedic Surgery, Meijo Hospital, Nagoya, 460-0001, Japan.
authors.forename: Noriaki
authors.initials: N
authors.lastname: Kawakami
authors.affiliation: Laboratory of Bone and Joint Diseases, Center for Integrative Medical Sciences, RIKEN, Tokyo, 160-8582, Japan.
authors.forename: Aritoshi
authors.initials: A
authors.lastname: Iida
authors.affiliation: Laboratory of Bone and Joint Diseases, Center for Integrative Medical Sciences, RIKEN, Tokyo, 160-8582, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nakajima
authors.affiliation: Laboratory of Bone and Joint Diseases, Center for Integrative Medical Sciences, RIKEN, Tokyo, 160-8582, Japan.|Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, 108-8639, Japan.
authors.forename: Yoji
authors.initials: Y
authors.lastname: Ogura
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Imagawa
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Miyake
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan.
authors.forename: Naomichi
authors.initials: N
authors.lastname: Matsumoto
authors.affiliation: Division of Cellular and Molecular Toxicology, National Institute of Health Sciences, Tokyo, 158-8501, Japan.
authors.forename: Yukuto
authors.initials: Y
authors.lastname: Yasuhiko
authors.affiliation: Department of Advanced Medicine for Spine and Spinal Cord Disorders, Hokkaido University Graduate School of Medicine, Sapporo, 060-8648, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Sudo
authors.affiliation: Department of Orthopaedic Surgery, Seirei Sakura Citizen Hospital, Sakura, 285-0825, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Kotani
authors.affiliation: Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, 108-8639, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, 108-8639, Japan.
authors.forename: Morio
authors.initials: M
authors.lastname: Matsumoto
authors.affiliation: Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, 108-8639, Japan.
authors.forename: Kota
authors.initials: K
authors.lastname: Watanabe
authors.affiliation: Laboratory of Bone and Joint Diseases, Center for Integrative Medical Sciences, RIKEN, Tokyo, 160-8582, Japan.
authors.forename: Shiro
authors.initials: S
authors.lastname: Ikegawa
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D002885:Chromosomes, Human, Pair 16; D000013:Congenital Abnormalities / Q000175:diagnosis / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D000073658:Loss of Function Mutation; D008297:Male; D010375:Pedigree; D010641:Phenotype; D011859:Radiography; D012600:Scoliosis / Q000175:diagnosis / Q000235:genetics*; D020825:T-Box Domain Proteins / Q000235:genetics*
chemical_list: D020825:T-Box Domain Proteins; C491182:TBX6 protein, human
keywords: 16p11.2 deletion; TBX6; compound heterozygosity; congenital scoliosis; haplotype; spondylocostal dysostosis