title: Identification and characterization of cryptic SHOX intragenic deletions in three Japanese patients with Léri-Weill dyschondrosteosis.
abstract: Although short-stature homeobox-containing gene (SHOX ) haploinsufficiency is responsible for Léri-Weill dyschondrosteosis (LWD), the molecular defect has not been identified in approximately 20% of Japanese LWD patients. Furthermore, although high prevalence of microdeletions affecting SHOX is primarily ascribed to the presence of repeat sequences such as Alu elements around SHOX, it remains to be determined whether microdeletions are actually mediated by repeat sequences. We performed multiple ligation probe amplification (MLPA) assay in six Japanese LWD patients with apparently normal SHOX, followed by fluorescent in situ hybridization (FISH) analysis and sequencing for polymerase chain reaction (PCR) products encompassing the deletion junctions in patients with abnormal MLPA patterns. Consequently, heterozygous intragenic deletions were identified in three cases, i.e., a 5,906-bp deletion involving exons 4-5 in case 1, a 5,594-bp deletion involving exons 4-6a in case 2, and a 50,199-bp deletion involving exons 4-6b in case 3. The deletion breakpoints of cases 1 and 2 were present in nonrepeat sequences, whereas those of case 3 resided within Alu elements. The results suggest that cryptic SHOX intragenic deletions account for a small fraction of LWD and that microdeletions affecting SHOX can be generated by repeat-sequence-mediated aberrant recombinations and by nonhomologous end joining.
authors.affiliation: Department of Endocrinology and Metabolism, National Research Institute for Child Health and Development, 2-10-1 Ohkura, Setagaya, Tokyo, 157-8535, Japan. mfukami@nch.go.jp.
authors.forename: Maki
authors.initials: M
authors.lastname: Fukami
authors.affiliation: Department of Endocrinology and Metabolism, National Research Institute for Child Health and Development, 2-10-1 Ohkura, Setagaya, Tokyo, 157-8535, Japan.|Department of Pediatrics, Nagasaki University School of Medicine, Nagasaki, Japan.
authors.forename: Sumito
authors.initials: S
authors.lastname: Dateki
authors.affiliation: Department of Endocrinology and Metabolism, National Research Institute for Child Health and Development, 2-10-1 Ohkura, Setagaya, Tokyo, 157-8535, Japan.
authors.forename: Fumiko
authors.initials: F
authors.lastname: Kato
authors.affiliation: Endocrinology and Metabolism Unit, Tokyo Metropolitan Kiyose Children's Hospital, Tokyo, Japan.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Hasegawa
authors.affiliation: Department of Endocrinology and Metabolism, Saitama Children's Medical Center, Saitama, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mochizuki
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 Endocrinology and Metabolism, National Research Institute for Child Health and Development, 2-10-1 Ohkura, Setagaya, Tokyo, 157-8535, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Ogata
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics; D001483:Base Sequence / Q000235:genetics*; D001827:Body Height / Q000235:genetics; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007564:Japan; D017880:Limb Deformities, Congenital / Q000235:genetics*; D010009:Osteochondrodysplasias / Q000235:genetics*; D017384:Sequence Deletion / Q000235:genetics*; D000074122:Short Stature Homeobox Protein
chemical_list: D018398:Homeodomain Proteins; C106071:SHOX protein, human; D000074122:Short Stature Homeobox Protein