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

Lippincott, Margaret F; Xu, Wanxue; Smith, Abigail A; Miao, Xinyu; Lafont, Agathe; Shennib, Omar; Farley, Gordon J; Sabbagh, Riwa; Delaney, Angela; Stamou, Maria; Plummer, Lacey; Salnikov, Kathryn; Georgopoulos, Neoklis A.; Mericq, Verónica; Quinton, Richard; Mau‐Them, Frédéric Tran; Nambot, Sophie; Hamad, Asma; Brittain, Helen; Tooze, Rebecca S.; Calpena, Eduardo; Wilkie, Andrew; Willems, Marjolaine; Crowley, William F.; Balasubramanian, Ravikumar; Lamarche-Vane, Nathalie; Davis, Erica E.; Seminara, Stephanie B.

doi:10.1016/j.gim.2022.08.025

Cited by 3 publications

(2 citation statements)

References 47 publications

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“…Combined with the observed interaction between Rap1a and ARHGAP35 in ESCs cultured on ECM of low stiffness, these results show that ARHGAP35 is a component of a core protein mechanotransduction pathway. Substantial research indicates that ARH-GAP35 is a member of a group of GTPase-activating proteins (RhoGAPs); it encodes p190A RhoGAP (p190A), the functions of which are related to cell adhesion, cell migration, gene transcription and protein translation [48][49][50]. It should be noted that inactivation of ARH-GAP35 leads to abnormal activation of RhoA in endometrial cancer and promotes the malignant transformation of tumor cells through the Hippo-Yap pathway [51], consistent with the conclusions reported in this study.…”

Section: Discussionmentioning

confidence: 99%

Extracellular matrix stiffness mediates uterine repair via the Rap1a/ARHGAP35/RhoA/F-actin/YAP axis

Zhang

Wang

et al. 2023

Cell Commun Signal

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The integrity of the structure and function of the endometrium is essential for the maintenance of fertility. However, the repair mechanisms of uterine injury remain largely unknown. Here, we showed that the disturbance of mechanical cue homeostasis occurs after uterine injury. Applying a multimodal approach, we identified YAP as a sensor of biophysical forces that drives endometrial regeneration. Through protein activation level analysis of the combinatorial space of mechanical force strength and of the presence of particular kinase inhibitors and gene silencing reagents, we demonstrated that mechanical cues related to extracellular matrix rigidity can turn off the Rap1a switch, leading to the inactivation of ARHGAP35and then induced activation of RhoA, which in turn depends on the polymerization of the agonist protein F-actin to activate YAP. Further study confirmed that mechanotransduction significantly accelerates remodeling of the uterus by promoting the proliferation of endometrial stromal cells in vitro and in vivo. These studies provide new insights into the dynamic regulatory mechanisms behind uterine remodeling and the function of mechanotransduction.

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Section: Discussionmentioning

confidence: 99%

Extracellular matrix stiffness mediates uterine repair via the Rap1a/ARHGAP35/RhoA/F-actin/YAP axis

Zhang

Wang

et al. 2023

Cell Commun Signal

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“…We created dorsal and lateral image templates, and imaged them live with VAST software (version 1.2.6.7) with >60% minimum similarity for the pattern-recognition algorithm. Bright field (Dorsal and lateral) images were acquired with the on-board camera and VAST software using default parameters as described [21,82,83] . Head size area and body length were measured on lateral bright field images with ImageJ (NIH) software (version 1.53a).…”

Section: Live Imaging Of Zebrafish Larvae and Bright Field Morphometricsmentioning

confidence: 99%

RNA methyltransferase SPOUT1/CENP-32 links mitotic spindle organization with the neurodevelopmental disorder SpADMiSS

Dharmadhikari,

Abad,

Khan

et al. 2024

Preprint

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SPOUT1/CENP-32 encodes a putative SPOUT RNA methyltransferase previously identified as a mitotic chromosome associated protein. SPOUT1/CENP-32 depletion leads to centrosome detachment from the spindle poles and chromosome misalignment. Aided by gene matching platforms, we identified 24 individuals with neurodevelopmental delays from 18 families with bi-allelic variants in SPOUT1/CENP-32 detected by exome/genome sequencing. Zebrafish spout1/cenp-32 mutants showed reduction in larval head size with concomitant apoptosis likely associated with altered cell cycle progression. In vivo complementation assays in zebrafish indicated that SPOUT1/CENP-32 missense variants identified in humans are pathogenic. Crystal structure analysis of SPOUT1/CENP-32 revealed that most disease-associated missense variants mapped to the catalytic domain. Additionally, SPOUT1/CENP-32 recurrent missense variants had reduced methyltransferase activity in vitro and compromised centrosome tethering to the spindle poles in human cells. Thus, SPOUT1/CENP-32 pathogenic variants cause an autosomal recessive neurodevelopmental disorder: SpADMiSS (SPOUT1 Associated Development delay Microcephaly Seizures Short stature) underpinned by mitotic spindle organization defects and consequent chromosome segregation errors.

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Genetic architecture of congenital hypogonadotropic hypogonadism: insights from analysis of a Portuguese cohort

Carriço,

Gonçalves,

Al-Naama

et al. 2024

Human Reproduction Open

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STUDY QUESTION What is the contribution of genetic defects in Portuguese patients with congenital hypogonadotropic hypogonadism (CHH)? SUMMARY ANSWER Approximately one-third of patients with CHH were found to have a genetic cause for their disorder, with causal pathogenic and likely pathogenic germline variants distributed among 10 different genes; cases of oligogenic inheritance were also included. WHAT IS KNOWN ALREADY CHH is a rare and genetically heterogeneous disorder characterized by deficient production, secretion, or action of GnRH, LH, and FSH, resulting in delayed or absent puberty, and infertility. STUDY DESIGN, SIZE, DURATION Genetic screening was performed on a cohort of 81 Portuguese patients with CHH (36 with Kallmann syndrome and 45 with normosmic hypogonadotropic hypogonadism) and 263 unaffected controls. PARTICIPANTS/MATERIALS, SETTING, METHODS The genetic analysis was performed by whole-exome sequencing followed by the analysis of a virtual panel of 169 CHH-associated genes. The main outcome measures were non-synonymous rare sequence variants (population allele frequency <0.01) classified as pathogenic, likely pathogenic, and variants of uncertain significance (VUS). MAIN RESULTS AND THE ROLE OF CHANCE A genetic cause was identified in 29.6% of patients. Causal pathogenic and likely pathogenic variants were distributed among 10 of the analysed genes. The most frequently implicated genes were GNRHR, FGFR1, ANOS1, and CHD7. Oligogenicity for pathogenic and likely pathogenic variants was observed in 6.2% of patients. VUS and oligogenicity for VUS variants were observed in 85.2% and 54.3% of patients, respectively, but were not significantly different from that observed in controls. LARGE SCALE DATA N/A. LIMITATIONS, REASONS FOR CAUTION The identification of a large number of VUS presents challenges in interpretation and these may require reclassification as more evidence becomes available. Non-coding and copy number variants were not studied. Functional studies of the variants were not undertaken. WIDER IMPLICATIONS OF THE FINDINGS This study highlights the genetic heterogeneity of CHH and identified several novel variants that expand the mutational spectrum of the disorder. A significant proportion of patients remained without a genetic diagnosis, suggesting the involvement of additional genetic, epigenetic, or environmental factors. The high frequency of VUS underscores the importance of cautious variant interpretation. These findings contribute to the understanding of the genetic architecture of CHH and emphasize the need for further studies to elucidate the underlying mechanisms and identify additional causes of CHH. STUDY FUNDING/COMPETING INTEREST(S) This research was funded by the Portuguese Foundation for Science and Technology (grant numbers PTDC/SAU-GMG/098419/2008, UIDB/00709/2020, CEECINST/00016/2021/CP2828/CT0002, and 2020.04924.BD) and by Sidra Medicine—a member of the Qatar Foundation (grant number SDR400038). The authors declare no competing interests.

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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

Cited by 3 publications

References 47 publications

Extracellular matrix stiffness mediates uterine repair via the Rap1a/ARHGAP35/RhoA/F-actin/YAP axis

Extracellular matrix stiffness mediates uterine repair via the Rap1a/ARHGAP35/RhoA/F-actin/YAP axis

RNA methyltransferase SPOUT1/CENP-32 links mitotic spindle organization with the neurodevelopmental disorder SpADMiSS

Genetic architecture of congenital hypogonadotropic hypogonadism: insights from analysis of a Portuguese cohort

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