Homozygosity for a rare GNRHR variant associated with isolated hypogonadotropic hypogonadism

Pereira-Caetano, Iris; Dias, Teresa; Garcia e Costa, Joaquim; Gonçalves, João

http://hdl.handle.net/10400.18/5094

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Authors

Pereira-Caetano, Iris

Dias, Teresa

Garcia e Costa, Joaquim

Gonçalves, João

Abstract(s)

Congenital disorders of sex development (DSD) can be explained by exposure to harmful environmental factors during fetal life, or by genetic conditions. Hereditary DSD can be due to genetic defects, hormonal synthesis and action. In 46,XY individuals, alterations affecting the hypothalamic-pituitary-gonadal (HPG) axis disturb testosterone synthesis resulting in DSD ranging from cryptorchidism to female external genitalia. The HPG axis can be disturbed by GNRH synthesis or action (through its receptor – GNRHR) causing hypogonadotropic hypogonadism (HH). Here, we describe a 46,XY male patient diagnosed at adult age with isolated HH, presenting low testicular volume, micropenis, gynecomastia, and low basal levels of testosterone, FSH and LH. At 6 years old he was submitted to orchiopexy. After informed consent, the patient’s GNRHR gene was analyzed by PCR and direct sequencing. Molecular results revealed a 3 nucleotides deletion, c.924_926delCTT, leading to the removal of Phenylalanine in position 309 (p.Phe309del) of the GNRHR protein transmembrane domain 7. Considering that Phe309 is very closed to Asn305 (which belongs to GNRHR binding pocket), Phe309del most probably disturbs intramolecular interactions resulting in changes in affinity for GNRH, in receptor folding or, in transmembrane domain interations. This unique homozygosity for c.924_926delCTT, ultimately may affect the intracellular signal transduction leading to a reduction in FSH and LH synthesis, explaining the patient’s HH.