title: Whole-exome sequencing identifies mutations of KIF22 in spondyloepimetaphyseal dysplasia with joint laxity, leptodactylic type.
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.
authors.affiliation: Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Byung-Joo
authors.initials: BJ
authors.lastname: Min
authors.forename: Namshin
authors.initials: N
authors.lastname: Kim
authors.forename: Taesu
authors.initials: T
authors.lastname: Chung
authors.forename: Ok-Hwa
authors.initials: OH
authors.lastname: Kim
authors.forename: Gen
authors.initials: G
authors.lastname: Nishimura
authors.forename: Chin Youb
authors.initials: CY
authors.lastname: Chung
authors.forename: Hae Ryong
authors.initials: HR
authors.lastname: Song
authors.forename: Hyun Woo
authors.initials: HW
authors.lastname: Kim
authors.forename: Hye Ran
authors.initials: HR
authors.lastname: Lee
authors.forename: Jiwoong
authors.initials: J
authors.lastname: Kim
authors.forename: Tae-Hoon
authors.initials: TH
authors.lastname: Kang
authors.forename: Myung-Eui
authors.initials: ME
authors.lastname: Seo
authors.forename: San-Deok
authors.initials: SD
authors.lastname: Yang
authors.forename: Do-Hwan
authors.initials: DH
authors.lastname: Kim
authors.forename: Seung-Bok
authors.initials: SB
authors.lastname: Lee
authors.forename: Jong-Il
authors.initials: JI
authors.lastname: Kim
authors.forename: Jeong-Sun
authors.initials: JS
authors.lastname: Seo
authors.forename: Ji-Yeob
authors.initials: JY
authors.lastname: Choi
authors.forename: Daehee
authors.initials: D
authors.lastname: Kang
authors.forename: Dongsup
authors.initials: D
authors.lastname: Kim
authors.forename: Woong-Yang
authors.initials: WY
authors.lastname: Park
authors.forename: Tae-Joon
authors.initials: TJ
authors.lastname: Cho
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000293:Adolescent; D020816:Amino Acid Motifs; D000818:Animals; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics*; D059472:Exome; D005260:Female; D015870:Gene Expression; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D004204:Joint Dislocations / Q000151:congenital* / Q000235:genetics; D007593:Joint Instability / Q000235:genetics*; D016547:Kinesins / Q000737:chemistry / Q000235:genetics*; D008297:Male; D051379:Mice; D008875:Middle Aged; D056004:Molecular Dynamics Simulation; D020125:Mutation, Missense; D009928:Organ Specificity; D010009:Osteochondrodysplasias / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA
chemical_list: D004268:DNA-Binding Proteins; C098764:KIF22 protein, human; D016547:Kinesins