Whole-exome sequencing identifies mutations of KIF22 in spondyloepimetaphyseal dysplasia with joint laxity, leptodactylic type |
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Authors: | Min Byung-Joo Kim Namshin Chung Taesu Kim Ok-Hwa Nishimura Gen Chung Chin Youb Song Hae Ryong Kim Hyun Woo Lee Hye Ran Kim Jiwoong Kang Tae-Hoon Seo Myung-Eui Yang San-Deok Kim Do-Hwan Lee Seung-Bok Kim Jong-Il Seo Jeong-Sun Choi Ji-Yeob Kang Daehee Kim Dongsup Park Woong-Yang Cho Tae-Joon |
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Affiliation: | 1Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Korea;2Department of Orthopaedic Surgery, Seoul National University College of Medicine, Seoul 110-799, Korea;3Korean Bioinformation Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, Korea;4Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea;5Department of Radiology, Ajou University Hospital, Suwon, Kyunggi 443-721, Korea;6Department of Pediatric Imaging, Tokyo Metropolitan Children's Medical Center, Kiyose, Tokyo 204-8567, Japan;7Department of Orthopaedic Surgery, Korea University Guro Hospital, Seoul 152-703, Korea;8Department of Orthopaedic Surgery, Yonsei University Severance Children's Hospital, Seoul 120-752, Korea |
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Abstract: | Spondyloepimetaphyseal dysplasia with joint laxity (SEMDJL), leptodactylic (lepto-SEMDJL) or Hall type, is an autosomal-dominant skeletal dysplasia manifesting with short stature, joint laxity with dislocation(s), limb malalignment, and spinal deformity. Its causative gene mutation has not yet been discovered. We captured and sequenced the exomes of eight affected individuals in six unrelated kindreds (three individuals in a family and five simplex individuals). Five novel sequence variants in KIF22, which encodes a member of the kinesin-like protein family, were identified in seven individuals. Sanger sequencing of KIF22 confirmed that c.443C>T (p.Pro148Ser) cosegregated with the phenotype in the affected individuals in the family; c.442C>T (p.Pro148Leu) or c.446G>A (p.Arg149Gln) was present in four of five simplex individuals, but was absent in unaffected individuals in their family and 505 normal cohorts. KIF22 mRNA was detected in human bone, cartilage, joint capsule, ligament, skin, and primary cultured chondrocytes. In silico analysis of KIF22 protein structure indicates that Pro148 and Arg149 are important in maintaining hydrogen bonds in the ATP binding and motor domains of KIF22. We conclude that these mutations in KIF22 cause lepto-SEMDJL. |
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