Heterozygous gain of function variant in GUCY1A2 may cause autonomous ovarian hyperfunction

Area of Science:

• Genetics
• Endocrinology
• Biochemistry

Background:

• Gain-of-function variants in guanylate cyclase genes can lead to endocrine disorders.
• The GUCY1A2 gene encodes a subunit of soluble guanylate cyclase, involved in cyclic nucleotide signaling.

Purpose of the Study:

• To characterize the phenotype associated with a de novo gain-of-function variant in the GUCY1A2 gene.
• To investigate the biochemical consequences of the GUCY1A2 p.(E486D) variant.

Main Methods:

• Exome sequencing identified the de novo GUCY1A2 variant c.1458G>T p.(E486D).
• In vitro assays assessed enzyme activity, nitric oxide and carbon monoxide response, and thermostability.
• Confocal microscopy examined subcellular localization of fluorescent protein-tagged constructs.

Main Results:

• The patient presented with precocious peripheral puberty and severe intellectual disability.
• The GUCY1A2 p.(E486D) variant showed increased nitric oxide affinity and decreased thermostability.
• Heme content, oxidation susceptibility, and subcellular localization were unaltered.

Conclusions:

• The GUCY1A2 p.(E486D) variant likely causes syndromic autonomous ovarian puberty due to increased cyclic guanosine monophosphate (cGMP).
• The ovarian phenotype overlaps with McCune-Albright syndrome, suggesting cGMP impacts the ovarian cAMP pathway.
• Further studies are needed to confirm the causal link.