ISSN 1662-4009 (online)

ESPE Yearbook of Paediatric Endocrinology (2022) 19 6.5 | DOI: 10.1530/ey.19.6.5


Eur J Endocrinol. 2021 Dec 1;186(1):65-72. PMID: 34714774, doi: 10.1530/EJE-21-0910.

Brief Summary: This brief report describes a novel gene, PPP2R3C, in the pathogenesis of complete and partial XY and XX gonadal dysgenesis (GD).

GD is a very rare condition with an estimated prevalence of 1–9 cases per 100,000 live-births. GD can be classified as either complete (CGD) or partial (PGD) depending on the clinical characteristics and gonadal morphology. A subgroup of patients with GD have additional syndromic features. So far, there are a small number of genes described in the etiology of syndromic GD including RSPO1, LARS2, HSD17B4, HARS2, TWNK, ERAL1, and CLPP in 46,XX, and ARX, ATRX, DHH, GATA4, HHAT, SOX9, WT1 and ZFPM2 in 46,XY patients. In 2019, PPP2R3C was included in the list of genetic causes of syndromic CGD in 46,XY, namely MEGD syndrome (Myo-Ectodermo-Gonadal Dysgenesis) (1). Besides XY-CGD, a number of extragonadal syndromic features, including typical facial gestalt, low birth weight, myopathy, rod and cone dystrophy, anal atresia, omphalocele, sensorineural hearing loss, dry and scaly skin, skeletal abnormalities, renal agenesis, and neuromotor delay characterize MEGD syndrome.

This brief report describes a homozygous c.578T>C (p.L193S) PPP2R3C variant identified in four patients from three unrelated families; one 46,XX girl with primary gonadal insufficiency, two girls with 46,XY CGD, and one undervirilised boy with 46,XY PGD. The developmental role of Ppp2r3c in mice (C57BL6/N) was explored using CRISPR/Cas9 genome editing. Ppp2r3c expression was identified in the majority of gonadal cell lineages, including Tcf21+ gonadal progenitors and Sox9+ and Fst+ supporting cells in XY and XX gonads, respectively. There was no evidence of sexual dimorphism in levels of expression. Low-level, widespread expression of Ppp2r3c during this period in a number of cell lineages that contribute to the gonadal supporting cells was consistent with a sex-determining function in mice. Heterozygous Ppp2r3c knockout mice appeared overtly normal and fertile. Inspection of homozygous embryos revealed evidence of dead embryos at various days post coitum which suggests that loss of function of Ppp2r3c is not compatible with viability in mice.

This report illustrates the association of PPP2R3C variants with GD of various severities both in 46,XX, and 46,XY individuals suggesting the critical role of PPP2R3C in human gonadal development. In the mouse model, Ppp2r3c is important for sex determination and has an essential role in development.

Reference: 1. Guran T, Yesil G, Turan S, Atay Z, Bozkurtlar E, Aghayev A, Gul S, Tinay I, Aru B, Arslan S, Koroglu MK, Ercan F, Demirel GY, Eren FS, Karademir B, Bereket A. PPP2R3C gene variants cause syndromic 46,XY gonadal dysgenesis and impaired spermatogenesis in humans. Eur J Endocrinol. 2019 May 1;180(5):291–309. doi: 10.1530/EJE-19-0067. PMID: 30893644.

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