Purpose: The purpose of this study was to characterize the phenotype associated with
a de novo gain-of-function variant in the GUCY1A2 gene. Methods: An individual carrying
the de novo heterozygous variant c.1458G>T p.(E486D) in GUCY1A2 was identified by
exome sequencing. The effect of the corresponding enzyme variant alpha 2E486D/beta
1 was evaluated using concentration-response measurements with wild-type enzyme and
the variant in cytosolic fractions of HEK293 cells, UV-vis absorbance spectra of the
corresponding purified enzymes, and examination of overexpressed fluorescent protein-tagged
constructs by confocal laser scanning microscopy. Results: The patient presented with
precocious peripheral puberty resembling the autonomous ovarian puberty seen in McCune-Albright
syndrome. Additionally, the patient displayed severe intellectual disability. In vitro
activity assays revealed an increased nitric oxide affinity for the mutant enzyme.
The response to carbon monoxide was unchanged, while thermostability was decreased
compared to wild type. Heme content, susceptibility to oxidation, and subcellular
localization upon overexpression were unchanged. Conclusion: Our data define a syndromic
autonomous ovarian puberty likely due to the activating allele p.(E486D) in GUCY1A2
leading to an increase in cGMP. The overlap with the ovarian symptoms of McCune-Albright
syndrome suggests an impact of this cGMP increase on the cAMP pathway in the ovary.
Additional cases will be needed to ensure a causal link.
