Expanding the spectrum of syndromic PPP2R3C‐related XY gonadal dysgenesis to XX gonadal dysgenesis

Abstract

Homozygous variants in PPP2R3C have been reported to cause a syndromic 46,XY complete gonadal dysgenesis phenotype with extragonadal manifestations (GDRM, MIM# 618419) in patients from four unrelated families, whereas heterozygous variants have been linked to reduced fertility with teratozoospermia (SPGF36, MIM# 618420) in male carriers. We present eight patients from four unrelated families of Turkish and Indian descent with three different germline homozygous PPP2R3C variants including a novel in-frame duplication (c.639_647dupTTTCTACTC, p. Ser216_Tyr218dup). All patients exhibit recognizable facial dysmorphisms allowing gestalt diagnosis. In two 46,XX patients with hypergonadotropic hypogonadism and nonvisualized gonads, primary amenorrhea along with absence of secondary sexual characteristics and/or unique facial gestalt led to the diagnosis. 46,XY affected individuals displayed a spectrum of external genital phenotypes from ambiguous genitalia to complete female. We expand the spectrum of syndromic PPP2R3C-related XY gonadal dysgenesis to both XY and XX gonadal dysgenesis. Our findings supported neither ocular nor muscular involvement as major criteria of the syndrome. We also did not encounter infertility problems in the carriers. Since both XX and XY individuals were affected, we hypothesize that PPP2R3C is essential in the early signaling cascades controlling sex determination in humans.

Case Report: Novel Compound Heterozygotic Variants in PPP2R3C Gene Causing Syndromic 46, XY Gonadal Dysgenesis and Literature Review

“…Thirteen 46, XY DSD patients had been reported in three articles previously ( Guran et al, 2019 ; Cicek et al, 2021 ; Altunoglu et al, 2022 ). All the patients came from the consanguineous marriage and had been identified as homozygous PPP2R3C variants.…”

A disease-associated PPP2R3C-MAP3K1 phospho-regulatory module controls centrosome function

“…Following our identification of Ppp2r3c in a screen for ciliary signaling mutants, pathogenic variants in PPP2R3C were reported in patients with a developmental syndrome characterized by 46-XY complete gonadal dysgenesis, facial dysmorphism, and retinal degeneration. [9][10][11] This myoectodermal gonadal dysgenesis (MEGD) syndrome (OMIM #618419) is a recessive disorder caused by mutations at conserved PPP2R3C residues L193S, F350S, or L103P (Fig. 4A).…”

“…Additionally, inactivating PPP2R3C mutations and activating MAP3K1 mutations both cause congenital syndromes characterized by gonadal dysgenesis. 9–15 As a syndromic PPP2R3C variant is defective in centriolar localization and binding to centriolar protein FOP, we propose that imbalanced activity of this centrosomal kinase-phosphatase pair is the shared cause of these disorders. Thus, our findings reveal a new centrosomal phospho-regulatory module, shed light on disorders of gonadal development, and illustrate the power of systems genetics to identify previously unrecognized gene functions.…”