title: Testicular dysgenesis/regression without campomelic dysplasia in patients carrying missense mutations and upstream deletion of SOX9.
abstract: SOX9 haploinsufficiency underlies campomelic dysplasia (CD) with or without testicular dysgenesis. Current understanding of the phenotypic variability and mutation spectrum of SOX9 abnormalities remains fragmentary. Here, we report three patients with hitherto unreported SOX9 abnormalities. These patients were identified through molecular analysis of 33 patients with 46,XY disorders of sex development (DSD). Patients 1-3 manifested testicular dysgenesis or regression without CD. Patients 1 and 2 carried probable damaging mutations p.Arg394Gly and p.Arg437Cys, respectively, in the SOX9 C-terminal domain but not in other known 46,XY DSD causative genes. These substitutions were absent from ~120,000 alleles in the exome database. These mutations retained normal transactivating activity for the Col2a1 enhancer, but showed impaired activity for the Amh promoter. Patient 3 harbored a maternally inherited ~491 kb SOX9 upstream deletion that encompassed the known 32.5 kb XY sex reversal region. Breakpoints of the deletion resided within nonrepeat sequences and were accompanied by a short-nucleotide insertion. The results imply that testicular dysgenesis and regression without skeletal dysplasia may be rare manifestations of SOX9 abnormalities. Furthermore, our data broaden pathogenic SOX9 abnormalities to include C-terminal missense substitutions which lead to target-gene-specific protein dysfunction, and enhancer-containing upstream microdeletions mediated by nonhomologous end-joining.
authors.affiliation: Department of Molecular Endocrinology National Research Institute for Child Health and Development Tokyo Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Katoh-Fukui
authors.affiliation: Department of Molecular Endocrinology National Research Institute for Child Health and Development Tokyo Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Igarashi
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 National Center for Child Health and Development Tokyo Japan.
authors.forename: Reiko
authors.initials: R
authors.lastname: Horikawa
authors.affiliation: Department of Pediatrics Dokkyo Medical University Koshigaya Hospital Koshigaya Japan.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Nagai
authors.affiliation: Department of Pediatrics Dokkyo Medical University Koshigaya Hospital Koshigaya Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Tsuchiya
authors.affiliation: Department of Molecular Endocrinology National Research Institute for Child Health and Development Tokyo Japan.
authors.forename: Erina
authors.initials: E
authors.lastname: Suzuki
authors.affiliation: Department of Molecular Endocrinology National Research Institute for Child Health and Development Tokyo Japan.
authors.forename: Mami
authors.initials: M
authors.lastname: Miyado
authors.affiliation: Department of Maternal-Fetal Biology National Research Institute for Child Health and Development Tokyo Japan.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Hata
authors.affiliation: Department of Maternal-Fetal Biology National Research Institute for Child Health and Development Tokyo Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakabayashi
authors.affiliation: Department of Maternal-Fetal Biology National Research Institute for Child Health and Development Tokyo Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Hayashi
authors.affiliation: National Research Institute for Child Health and Development Tokyo Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Matsubara
authors.affiliation: Department of Molecular Biology Graduate School of Medical Sciences Kyushu University Fukuoka Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Baba
authors.affiliation: Department of Molecular Biology Graduate School of Medical Sciences Kyushu University Fukuoka Japan.
authors.forename: Ken-Ichirou
authors.initials: K
authors.lastname: Morohashi
authors.affiliation: Department of Systems BioMedicine National Research Institute for Child Health and Development Tokyo Japan.
authors.forename: Arisa
authors.initials: A
authors.lastname: Igarashi
authors.affiliation: Department of Molecular EndocrinologyNational Research Institute for Child Health and DevelopmentTokyoJapan; Department of PediatricsHamamatsu University School of MedicineHamamatsuJapan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Ogata
authors.affiliation: Department of Systems BioMedicine National Research Institute for Child Health and Development Tokyo Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Takada
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
keywords: Campomelic dysplasia; deletion; enhancer; mutation; testis