A novel mutation in SOX2 causes hypogonadotropic hypogonadism with mild ocular malformation.
BACKGROUND
Heterozygous SOX2 mutations have been reported to cause isolated hypogonadotropic hypogonadism (HH) in addition to ocular and brain abnormalities.


OBJECTIVE
We report a novel missense SOX2 (Y110C) mutation in an HH patient with mild ocular malformation.


METHODS
The 20-year-old male was referred because of typical signs of complete hypogonadism, with small intrascrotal testes (2 ml), no pubic hair (P1), and a micropenis. Hormone assays revealed very low plasma testosterone levels and very low levels of plasma gonadotropin. He was found to have retinal detachment in his right eye and surgery was performed at the age of 14 years.


RESULTS
Using a next-generation sequencing strategy, we identified a novel heterozygous SOX2 mutation, c.329A>G (p.Y110C). Y110C SOX2 had reduced transactivation and no dominant negative effect. Subcellular localization revealed no significant difference between wild-type and mutant SOX2. EMSA experiments showed that the Y110C SOX2 abrogated DNA-binding ability.


CONCLUSIONS
The Y110C mutation affects a critical residue in the SOX2 protein. This study extends our understanding of the phenotypic features, molecular mechanism, and developmental course associated with mutations in SOX2. When multiple genes need to be analyzed for mutations simultaneously, targeted sequence analysis of interesting genomic regions is an attractive approach.
Department of Pediatrics, Keio University School of Medicine Tokyo, Tokyo, Japan.
Masaki
M
Takagi
Satoshi
S
Narumi
Yumi
Y
Asakura
Koji
K
Muroya
Yukihiro
Y
Hasegawa
Masanori
M
Adachi
Tomonobu
T
Hasegawa
D006579:Heterozygote; D006801:Humans; D007006:Hypogonadism / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense / Q000235:genetics*; D010641:Phenotype; D012163:Retinal Detachment / Q000235:genetics*; D055748:SOXB1 Transcription Factors / Q000235:genetics*; D055815:Young Adult
C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors