SRY gene

**Molecular basis** - Location: Yp11.3 (short arm of Y chromosome). Single-exon gene. - Product: SRY protein = testis-determining factor (TDF), a transcription factor with an HMG box that binds and bends DNA. - Key downstream target: SOX9 (upregulated by SRY with SF1). SOX9 promotes Sertoli cell differentiation and also induces FGF9 and AMH. Without SRY, the default pathway is ovarian development (WNT4, RSPO1, DAX1/NR0B1 and FOXL2 support the ovarian pathway).

**Normal male development sequence** 1. SRY is expressed in the bipotential gonad around weeks 6-7 of gestation. 2. Sertoli cells develop and secrete anti-Müllerian hormone (AMH, also called MIS). AMH causes ipsilateral regression of the paramesonephric (Müllerian) ducts (uterus, fallopian tubes, upper vagina). 3. Leydig cells secrete testosterone, which stimulates the mesonephric (Wolffian) ducts to form the epididymis, vas deferens, seminal vesicles and ejaculatory ducts. 4. Dihydrotestosterone (DHT, made from testosterone by 5-alpha-reductase) drives external genitalia (penis, scrotum, prostate).

**Clinical correlations (high-yield)** - **Swyer syndrome (46,XY complete gonadal dysgenesis):** SRY mutation or deletion. The phenotype is female, with normal external genitalia and a present uterus and tubes (no AMH), but streak gonads. Presents with primary amenorrhea and absent secondary sexual characteristics. Elevated FSH/LH, low estrogen. Gonadectomy is needed because of the high risk of gonadoblastoma/dysgerminoma. Hormone replacement therapy is given, and pregnancy is possible with donor oocytes. - **46,XX testicular DSD (de la Chapelle syndrome):** SRY translocated to the X chromosome or an autosome, usually by unequal crossover during paternal meiosis (Xp-Yp exchange). Phenotype is male with small testes, azoospermia and infertility. Gynecomastia may occur. No Y-linked AZF genes, so there is no spermatogenesis. Can resemble Klinefelter syndrome. - **Klinefelter syndrome (47,XXY):** Has SRY, so the phenotype is male. Seminiferous tubule dysgenesis, tall stature, hypogonadism and gynecomastia. - **Turner syndrome (45,X):** No SRY, so female phenotype with streak ovaries. - **True hermaphroditism (ovotesticular DSD):** Both ovarian and testicular tissue; may be due to SRY mosaicism or translocation. - **Androgen insensitivity syndrome (46,XY):** SRY is normal and testes are present, so AMH is made. The defect is the androgen receptor, giving a female external phenotype with a blind-ending vagina and absent uterus. Do not confuse this with Swyer syndrome, in which a uterus is present. - **5-alpha-reductase deficiency (46,XY):** SRY is normal. Low DHT leads to ambiguous genitalia at birth, with virilization at puberty.

**Exam pearls** - SRY determines gonadal sex. Hormones (AMH, testosterone and DHT) determine the phenotypic/ductal sex. - Mnemonic: "SRY = Sex-determining Region Y." SRY → SOX9 → Sertoli cells → AMH. - Karyotype and phenotype can be discordant. Always check for SRY and a uterus to distinguish Swyer from AIS. - FISH or PCR for SRY identifies Y material in DSD workups. - Sex chromosome mosaicism with Y material (e.g., 45,X/46,XY) carries a risk of gonadoblastoma, so gonadectomy is considered.