Testicular dysgenesis/regression without campomelic dysplasia in patients carrying missense mutations and upstream deletion of sox9

Yuko Katoh-Fukui, Maki Igarashi, Keisuke Nagasaki, Reiko Horikawa, Toshiro Nagai, Takayoshi Tsuchiya, Erina Suzuki, Mami Miyado, Kenichiro Hata, Kazuhiko Nakabayashi, Keiko Hayashi, Yoichi Matsubara, Takashi Baba, Ken Ichirou Morohashi, Arisa Igarashi, Tsutomu Ogata, Shuji Takada, Maki Fukami

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)550-557
Number of pages8
JournalMolecular Genetics and Genomic Medicine
Issue number6
Publication statusPublished - Nov 2015

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


Dive into the research topics of 'Testicular dysgenesis/regression without campomelic dysplasia in patients carrying missense mutations and upstream deletion of sox9'. Together they form a unique fingerprint.

Cite this