{Reference Type}: Journal Article
{Title}: The p190 RhoGAPs, ARHGAP35, and ARHGAP5 are implicated in GnRH neuronal development: Evidence from patients with idiopathic hypogonadotropic hypogonadism, zebrafish, and in vitro GAP activity assay.
{Author}: Lippincott MF;Xu W;Smith AA;Miao X;Lafont A;Shennib O;Farley GJ;Sabbagh R;Delaney A;Stamou M;Plummer L;Salnikov K;Georgopoulos NA;Mericq V;Quinton R;Mau-Them FT;Nambot S;Hamad A;Brittain H;Tooze RS;Calpena E;Wilkie AOM;Willems M;Crowley WF;Balasubramanian R;Lamarche-Vane N;Davis EE;Seminara SB;
{Journal}: Genet Med
{Volume}: 24
{Issue}: 12
{Year}: 12 2022
{Factor}: 8.864
{DOI}: 10.1016/j.gim.2022.08.025
{Abstract}: The study aimed to identify novel genes for idiopathic hypogonadotropic hypogonadism (IHH).<BR>A cohort of 1387 probands with IHH underwent exome sequencing and de novo, familial, and cohort-wide investigations. Functional studies were performed on 2 p190 Rho GTPase-activating proteins (p190 RhoGAP), ARHGAP35 and ARHGAP5, which involved in vivo modeling in larval zebrafish and an in vitro p190A-GAP activity assay.<BR>Rare protein-truncating variants (PTVs; n = 5) and missense variants in the RhoGAP domain (n = 7) in ARHGAP35 were identified in IHH cases (rare variant enrichment: PTV [unadjusted P = 3.1E-06] and missense [adjusted P = 4.9E-03] vs controls). Zebrafish modeling using gnrh3:egfp phenotype assessment showed that mutant larvae with deficient arhgap35a, the predominant ARHGAP35 paralog in the zebrafish brain, display decreased GnRH3-GFP+ neuronal area, a readout for IHH. In vitro GAP activity studies showed that 1 rare missense variant [ARHGAP35 p.(Arg1284Trp)] had decreased GAP activity. Rare PTVs (n = 2) also were discovered in ARHGAP5, a paralog of ARHGAP35; however, arhgap5 zebrafish mutants did not display significant GnRH3-GFP+ abnormalities.<BR>This study identified ARHGAP35 as a new autosomal dominant genetic driver for IHH and ARHGAP5 as a candidate gene for IHH. These observations suggest a novel role for the p190 RhoGAP proteins in GnRH neuronal development and integrity.