A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
Compound heterozygous mutations in the luteinizing hormone receptor signal peptide causing 46, XY disorder of sex development
Tekijät: Iulia Potorac, Ashutosh Trehan, Kamila Szymańska, Julie Fudvoye, Albert Thiry, Ilpo Huhtaniemi, Adrian F. Daly, Albert Beckers, Anne-Simone Parent, Adolfo Rivero-Müller
Kustantaja: BIOSCIENTIFICA LTD
Julkaisuvuosi: 2019
Journal: European Journal of Endocrinology
Tietokannassa oleva lehden nimi: EUROPEAN JOURNAL OF ENDOCRINOLOGY
Lehden akronyymi: EUR J ENDOCRINOL
Vuosikerta: 181
Numero: 2
Aloitussivu: K11
Lopetussivu: K20
Sivujen määrä: 10
ISSN: 0804-4643
DOI: https://doi.org/10.1530/EJE-19-0170
Tiivistelmä
Testosterone production by the fetal testis depends on a functional relationship between hCG and the LH/chorionic gonadotropin receptor (LHCGR). Failure of the receptor to correctly respond to its ligand leads to impaired sexual differentiation in males. A phenotypically female patient with pubertal delay had a 46, XY karyotype and was diagnosed with 46, XY disorder of sex development (DSD). Novel compound heterozygous LHCGR mutations were found in the signal peptide: a duplication p.L10_Q17dup of maternal origin, and a deletion (p.K12_L15del) and a p.L16Q missense mutation of paternal origin. cAMP production was very low for both the deletion and duplication mutations and was halved for the missense mutant. The duplication and missense mutations were both expressed intracellularly, but at very low levels at the cell membrane; they were most likely retained in the endoplasmic reticulum. The deletion mutant had a very limited intracellular expression, indicating impaired biosynthesis. There was reduced expression of all three mutants, which was most marked for the deletion mutation. There was also decreased protein expression of all three mutant receptors. In the deletion mutation, the presence of a lower-molecular-weight band corresponding to LHCGR monomer, probably due to lack of glycosylation, and a lack of bands corresponding to dimers/oligomers suggests absent ER entry. This novel case of 46, XY DSD illustrates how different LHCGR signal peptide mutations led to complete receptor inactivation by separate mechanisms. The study underlines the importance of specific regions of signal peptides and expands the spectrum of LHCGR mutations.
Testosterone production by the fetal testis depends on a functional relationship between hCG and the LH/chorionic gonadotropin receptor (LHCGR). Failure of the receptor to correctly respond to its ligand leads to impaired sexual differentiation in males. A phenotypically female patient with pubertal delay had a 46, XY karyotype and was diagnosed with 46, XY disorder of sex development (DSD). Novel compound heterozygous LHCGR mutations were found in the signal peptide: a duplication p.L10_Q17dup of maternal origin, and a deletion (p.K12_L15del) and a p.L16Q missense mutation of paternal origin. cAMP production was very low for both the deletion and duplication mutations and was halved for the missense mutant. The duplication and missense mutations were both expressed intracellularly, but at very low levels at the cell membrane; they were most likely retained in the endoplasmic reticulum. The deletion mutant had a very limited intracellular expression, indicating impaired biosynthesis. There was reduced expression of all three mutants, which was most marked for the deletion mutation. There was also decreased protein expression of all three mutant receptors. In the deletion mutation, the presence of a lower-molecular-weight band corresponding to LHCGR monomer, probably due to lack of glycosylation, and a lack of bands corresponding to dimers/oligomers suggests absent ER entry. This novel case of 46, XY DSD illustrates how different LHCGR signal peptide mutations led to complete receptor inactivation by separate mechanisms. The study underlines the importance of specific regions of signal peptides and expands the spectrum of LHCGR mutations.
Turun yliopiston Tutkimustietojärjestelmän portaali