%0 Journal Article
%T 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.
%A Lippincott MF
%A Xu W
%A Smith AA
%A Miao X
%A Lafont A
%A Shennib O
%A Farley GJ
%A Sabbagh R
%A Delaney A
%A Stamou M
%A Plummer L
%A Salnikov K
%A Georgopoulos NA
%A Mericq V
%A Quinton R
%A Mau-Them FT
%A Nambot S
%A Hamad A
%A Brittain H
%A Tooze RS
%A Calpena E
%A Wilkie AOM
%A Willems M
%A Crowley WF
%A Balasubramanian R
%A Lamarche-Vane N
%A Davis EE
%A Seminara SB
%J Genet Med
%V 24
%N 12
%D 12 2022
%M 36178483
%F 8.864
%R 10.1016/j.gim.2022.08.025
%X 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.