Mutations within Sox2/SOX2 are associated with abnormalities in the hypothalamo-pituitary-gonadal axis in mice and humans

Abstract

The transcription factor SOX2 is expressed most notably in the developing CNS and placodes, where it plays critical roles in embryogenesis. Heterozygous de novo mutations in SOX2 have previously been associated with bilateral anophthalmia/microphthalmia, developmental delay, short stature, and male genital tract abnormalities. Here we investigated the role of Sox2 in murine pituitary development. Mice heterozygous for a targeted disruption of Sox2 did not manifest eye defects, but showed abnormal anterior pituitary development with reduced levels of growth hormone, luteinizing hormone, and thyroid-stimulating hormone. Consequently, we identified 8 individuals (from a cohort of 235 patients) with heterozygous sequence variations in SOX2. Six of these were de novo mutations, predicted to result in truncated protein products, that exhibited partial or complete loss of function (DNA binding, nuclear translocation, or transactivation). Clinical evaluation revealed that, in addition to bilateral eye defects, SOX2 mutations were associated with anterior pituitary hypoplasia and hypogonadotropic hypogonadism, variable defects affecting the corpus callosum and mesial temporal structures, hypothalamic hamartoma, sensorineural hearing loss, and esophageal atresia. Our data show that SOX2 is necessary for the normal development and function of the hypothalamo-pituitary and reproductive axes in both humans and mice. Introduction SOX2 is a member of the sex-determining region of the Y chromosome-related (SRY-related) high-mobility group (HMG) box (SOX) family of transcription factors, encoded by 20 genes in humans and mice, each of which carries a 79-amino acid HMG box DNA-binding domain similar to that of SRY as well as domains implicated in transcriptional regulation (1, 2). Based on HMG box homology, they are grouped into different subfamilies. SOX1, SOX2, and SOX3 belong to the B1 subfamily and are expressed in various phases of embryonic development and cell differentiation, where they play critical roles in embryogenesis (3, 4). All 3 mark neuroepithelial progenitors and stem cells from the earliest stages of development, and there is a strong, but not absolute, tendency for them to be downregulated as cells differentiate.In the mouse, Sox2 RNA is first detected in cells at the morula stage (2.5 dpc) and then in the inner cell mass of the blastocyst (3.5 dpc).

Novel SOX2 partner-factor domain mutation in a four-generation family

“…In the patient groups reported, there are only a few cases in which colobomata have been described and in most of these they are not reported to be typical optic fissure closure defect colobomata. 8,9,18 More usual associated ocular features when present are cataract and the more severe ocular anomaly of sclerocornea. 1,8,9 It is possible that severe abnormalities, such as anophthalmia, severe microphthalmia or marked abnormality of the early lens and anterior segment, are caused by loss-of-function mutations such as truncating, frameshift and HMG domain mutations that primarily affect SOX2 function in very early eye development.…”

Testicular dysgenesis/regression without campomelic dysplasia in patients carrying missense mutations and upstream deletion of SOX9

“…2006). Briefly, an expression vector for wild‐type SOX9 was purchased from Origene Technologies (RC208944, Rockville, MD), and each SOX9 mutation was introduced into the expression vector by site‐directed mutagenesis (PrimeSTAR Mutagenesis Basal Kit; Takara Bio, Ohtsu, Japan).…”

SOX2 primes the epigenetic landscape in neural precursors enabling proper gene activation during hippocampal neurogenesis

“…Sex-determining region Y (SRY)-related HMG box 2 (SOX2) is a member of the SOXB1 family of transcription factors, which play important roles in maintaining neural stem/progenitor cell properties, including their capacity to proliferate and self-renew (7,8). In humans, SOX2 mutations are associated with anophthalmia, defective hippocampal development, and seizures (9)(10)(11). Most patients with this syndrome experience intellectual disabilities (11), suggesting that loss of SOX2 function affects areas of the brain involved in cognition (e.g., hippocampus).…”