Whole-Exome Sequencing Identifies Mutations of KIF22 in Spondyloepimetaphyseal Dysplasia with Joint Laxity, Leptodactylic Type

• Published in: American journal of human genetics 2011-12, Vol.89 (6), p.760-766
• Main 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
• Format: Article
• Language: English
• Subjects: Abnormalities, Multiple - genetics; Adolescent; Amino Acid Motifs; Animals; Biological and medical sciences; Case-Control Studies; Child; Child, Preschool; Deformities; DNA-Binding Proteins - chemistry; DNA-Binding Proteins - genetics; Exome; Female; Fundamental and applied biological sciences. Psychology; Gene Expression; General aspects. Genetic counseling; Genetic Association Studies; Genetics of eukaryotes. Biological and molecular evolution; Genotype; Humans; Joint Dislocations - congenital; Joint Dislocations - genetics; Joint Instability - genetics; Joints; Kinesin - chemistry; Kinesin - genetics; Male; Medical genetics; Medical sciences; Mice; Middle Aged; Molecular and cellular biology; Molecular Dynamics Simulation; Mutation; Mutation, Missense; Organ Specificity; Osteochondrodysplasias - genetics; Pedigree; Polymorphism, Single Nucleotide; Proteins; Sequence Analysis, DNA; Spine
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2011.10.015

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.