PUBLICATION
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
- Authors
- Lippincott, M.F., Xu, W., Smith, A.A., Miao, X., Lafont, A., Shennib, O., Farley, G.J., Sabbagh, R., Delaney, A., Stamou, M., Plummer, L., Salnikov, K., Georgopoulos, N.A., Mericq, V., Quinton, R., Mau-Them, F.T., Nambot, S., Hamad, A., Brittain, H., Tooze, R.S., Calpena, E., Wilkie, A.O.M., Willems, M., Crowley, W.F., Balasubramanian, R., Lamarche-Vane, N., Davis, E.E., Seminara, S.B.
- ID
- ZDB-PUB-221001-6
- Date
- 2022
- Source
- Genetics in medicine : official journal of the American College of Medical Genetics 24(12): 2501-2515 (Journal)
- Registered Authors
- Davis, Erica
- Keywords
- Developmental disorder, Idiopathic hypogonadotropic hypogonadism, Intellectual disability, Puberty, Rho GTPase–activating protein
- MeSH Terms
-
- Animals
- GTPase-Activating Proteins/genetics
- Gonadotropin-Releasing Hormone/genetics
- Guanine Nucleotide Exchange Factors
- Humans
- Hypogonadism*/genetics
- Repressor Proteins
- Zebrafish*/genetics
- PubMed
- 36178483 Full text @ Genet. Med.
Citation
Lippincott, M.F., Xu, W., Smith, A.A., Miao, X., Lafont, A., Shennib, O., Farley, G.J., Sabbagh, R., Delaney, A., Stamou, M., Plummer, L., Salnikov, K., Georgopoulos, N.A., Mericq, V., Quinton, R., Mau-Them, F.T., Nambot, S., Hamad, A., Brittain, H., Tooze, R.S., Calpena, E., Wilkie, A.O.M., Willems, M., Crowley, W.F., Balasubramanian, R., Lamarche-Vane, N., Davis, E.E., Seminara, S.B. (2022) 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. Genetics in medicine : official journal of the American College of Medical Genetics. 24(12):2501-2515.
Abstract
Purpose The study aimed to identify novel genes for idiopathic hypogonadotropic hypogonadism (IHH).
Methods 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.
Results 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.
Conclusion 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping