Compound heterozygous mutations in the luteinizing hormone receptor signal peptide causing 46,XY disorder of sex development

Abstract

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.

Rare copy number variants in ASTN2 gene in patients with neurodevelopmental disorders

“…The primary transcript could be processed in a different mRNA with a double copy of exon 1 and be translated in a protein with two copies of the SP. A recent work reported an association between a duplication in the SP of the LH/chorionic gonadotropin receptor and very low levels of the receptor at the cell membrane (Potorac et al ., 2019). Since an additional role for the unusual long SP of ASTN2 has been hypothesized, mutations in this region may affect not only the signaling function but also this additional function (Chang, 2017; Lara et al ., 2019).…”

Mitochondrial Dynamics as Potential Modulators of Hormonal Therapy Effectiveness in Males

“…This means that there are LHCGR variants that show defective biosynthesis (e.g., premature stop codon), while others show defective trafficking towards the endoplasmic reticulum or cell membrane and, finally, defective hormone binding and/or receptor activation. Several mutations affecting the signal peptide (e.g., p.L10P [ 72 , 73 ], p.L16Q, p.L10_Q17dup, p.K12_L15del [ 74 ]) or the extracellular and transmembrane domain [ 75 ] cause intracellular retention at cytoplasmic or endoplasmic reticulum level, leading to receptor degradation. Other LHCGR variants with mutated extracellular domain usually show reduced or null binding affinity towards both or selectively to one of the two ligands (e.g., p.C131R, p.I152T [ 75 ]).…”