title: Systematic molecular analyses of SHOX in Japanese patients with idiopathic short stature and Leri-Weill dyschondrosteosis.
abstract: The etiology of idiopathic short stature (ISS) and Leri-Weill dyschondrosteosis (LWD) in European patients is known to include SHOX mutations and copy-number variations (CNVs) involving SHOX and/or the highly evolutionarily conserved non-coding DNA elements (CNEs) flanking the gene. However, the frequency and types of SHOX abnormalities in non-European patients and the clinical importance of mutations in the CNEs remains to be clarified. Here, we performed systematic molecular analyses of SHOX for 328 Japanese patients with ISS or LWD. SHOX abnormalities accounted for 3.8% of ISS and 50% of LWD cases. CNVs around SHOX were identified in 16 cases, although the ~47 kb deletion frequently reported in European patients was absent in our cases. Probably damaging mutations and benign/silent substitutions were detected in four cases, respectively. Although CNE-linked substitutions were detected in 15 cases, most of them affected poorly conserved nucleotides and were shared by unaffected individuals. These results suggest that the frequency and mutation spectrum of SHOX abnormalities are comparable between Asian and European patients, with the exception of a European-specific downstream deletion. Furthermore, this study highlights the clinical importance and genetic heterogeneity of the SHOX-flanking CNVs, and indicates a limited clinical significance of point mutations in the CNEs.
authors.affiliation: Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.|Department of Advanced Pediatric Medicine, Tohoku University School of Medicine, Tokyo, Japan.
authors.forename: Hirohito
authors.initials: H
authors.lastname: Shima
authors.affiliation: Tanaka Growth Clinic, Tokyo, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Department of Pediatrics, Shizuoka City Shimizu Hospital, Shizuoka, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Kamimaki
authors.affiliation: Department of Pediatrics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Sumito
authors.initials: S
authors.lastname: Dateki
authors.affiliation: Department of Endocrinology and Metabolism, Kanagawa Children's Medical Center, Yokohama, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Muroya
authors.affiliation: Division of Endocrinology and Metabolism, National Center for Child Health and Development, Tokyo, Japan.
authors.forename: Reiko
authors.initials: R
authors.lastname: Horikawa
authors.affiliation: Department of Pediatrics, Tohoku University School of Medicine, Sendai, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Kanno
authors.affiliation: Department of Endocrinology and Metabolism, Kanagawa Children's Medical Center, Yokohama, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Adachi
authors.affiliation: Division of Endocrinology and Metabolism, National Center for Child Health and Development, Tokyo, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Naiki
authors.affiliation: Department of Pediatrics, Okayama Saiseikai General Hospital, Okayama, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: Department of Child Development, Kumamoto University Hospital, Kumamoto, Japan.
authors.forename: Hiroyo
authors.initials: H
authors.lastname: Mabe
authors.affiliation: Department of Pediatrics, Faculty of Medicine, University of Yamanashi, Chuo, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Yagasaki
authors.affiliation: Department of Pediatrics, Tohoku University School of Medicine, Sendai, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Kure
authors.affiliation: Department of Advanced Pediatric Medicine, Tohoku University School of Medicine, Tokyo, Japan.|National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Matsubara
authors.affiliation: Department of Pediatrics, Hokkaido University School of Medicine, Sapporo, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Tajima
authors.affiliation: Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Kashimada
authors.affiliation: Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Ishii
authors.affiliation: Department of Endocrinology and Metabolism, Kanagawa Children's Medical Center, Yokohama, Japan.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Asakura
authors.affiliation: Environment and Genome Research Center, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Ikuma
authors.initials: I
authors.lastname: Fujiwara
authors.affiliation: Department of Pediatrics, St Marianna University School of Medicine, Kawasaki, Japan.
authors.forename: Shun
authors.initials: S
authors.lastname: Soneda
authors.affiliation: Division of Pediatrics, Department of Homeostatic Regulation and Development, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Nagasaki
authors.affiliation: Division of Endocrinology and Metabolism, Aichi Children's Health and Medical Center, Obu, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Hamajima
authors.affiliation: Division of Pediatrics and Perinatology, Tottori University Faculty of Medicine, Yonago, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Kanzaki
authors.affiliation: Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Jinno
authors.affiliation: Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Ogata
authors.affiliation: Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Fukami
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D056915:DNA Copy Number Variations; D004392:Dwarfism / Q000175:diagnosis* / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D018740:Genetic Heterogeneity; D014644:Genetic Variation; D006130:Growth Disorders / Q000175:diagnosis* / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007223:Infant; D007564:Japan; D008297:Male; D009154:Mutation; D010009:Osteochondrodysplasias / Q000175:diagnosis* / Q000235:genetics*; D010641:Phenotype; D017422:Sequence Analysis, DNA; D000074122:Short Stature Homeobox Protein; D013577:Syndrome
chemical_list: D018398:Homeodomain Proteins; C106071:SHOX protein, human; D000074122:Short Stature Homeobox Protein