Open AccessTesticular dysgenesis/regression without campomelic dysplasia in patients carrying missense mutations and upstream deletion of SOX 9
Author(s) -
KatohFukui Yuko,
Igarashi Maki,
Nagasaki Keisuke,
Horikawa Reiko,
Nagai Toshiro,
Tsuchiya Takayoshi,
Suzuki Erina,
Miyado Mami,
Hata Kenichiro,
Nakabayashi Kazuhiko,
Hayashi Keiko,
Matsubara Yoichi,
Baba Takashi,
Morohashi Kenichirou,
Igarashi Arisa,
Ogata Tsutomu,
Takada Shuji,
Fukami Maki
Publication year - 2015
Publication title -
molecular genetics and genomic medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.765
H-Index - 29
ISSN - 2324-9269
DOI - 10.1002/mgg3.165
Subject(s) - missense mutation , haploinsufficiency , biology , genetics , exon , gonadal dysgenesis , dysgenesis , mutation , enhancer , gene , phenotype , endocrinology , transcription factor
SOX 9 haploinsufficiency underlies campomelic dysplasia (CD) with or without testicular dysgenesis. Current understanding of the phenotypic variability and mutation spectrum of SOX 9 abnormalities remains fragmentary. Here, we report three patients with hitherto unreported SOX 9 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 SOX 9 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 SOX 9 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 SOX 9 abnormalities. Furthermore, our data broaden pathogenic SOX 9 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.