Rabconnectin-3α is required for the morphological maturation of GnRH neurons and kisspeptin responsiveness

Tata, Brooke; Harbulot, Carole; Peineau, Stéphane; Jacquier, Sandrine; Roux, Nicolas de

doi:10.1038/srep42463

Cited by 16 publications

(13 citation statements)

References 41 publications

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“…RAB3GAP2 is a GTPase-activating protein, known to form a complex with RAB3GAP1 that together regulates the GTP hydrolysis activity of the Rab protein family of small GTPase(s) with putative exocytotic roles (Handley and Aligianis 2012). Our observations that RAB3GAP2-related MS is associated with hypogonadotropic hypogonadism are consistent with the previously reported interaction of RAB3GAP2 with rabconnectin 3a, a protein expressed in exocytosis vesicles in gonadotropin-releasing hormone (GnRH) axonal terminals in the median eminence of the hypothalamus and in the cells expressing luteinizing hormone (LH) and follicle-stimulating hormone (FSH) within the anterior pituitary gonadotropin-producing cells (Tata et al 2014(Tata et al , 2017. Therefore, we hypothesize that RAB3GAP2-associated hypogonadotropic hypogonadism may also result from defects in hormone release at the hypothalamic and/or pituitary levels.…”

Section: Discussionsupporting

confidence: 89%

Hypogonadotropic hypogonadism due to variants in RAB3GAP2: expanding the phenotypic and genotypic spectrum of Martsolf syndrome

Plummer

Quinton

et al. 2020

Cold Spring Harb Mol Case Stud

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Biallelic pathogenic variants in RAB3GAP2 cause Warburg Micro syndrome (WARBM) and Martsolf syndrome (MS), two rare, phenotypically overlapping disorders characterized by congenital cataracts, intellectual disability, and hypogonadism. Although the initial report documented hypergonadotropic hypogonadism (implying a gonadal defect), an adolescent girl with WARBM/MS was subsequently reported to have hypogonadotropic hypogonadism (implying a central defect in either the hypothalamus or anterior pituitary). However, in adult MS, hypogonadotropism has not been convincingly demonstrated. Additionally, the correlation between the pathogenic severity of variants in RAB3GAP2 and the phenotypic severity also remains unclear. Here we present a clinical report of a woman with congenital cataracts, apparent intellectual disability, and pubertal failure who underwent exome sequencing (ES) to determine a precise molecular diagnosis. Reproductive phenotypes reported previously in individuals with MS and the genotypic spectrum of previous RAB3GAP2 variants were also reviewed. The ES identified pathogenic compound heterozygous RAB3GAP2 variants (c.387-2A > G; p.(Arg428Glu)) combined with her phenotypic features, which enabled a unifying molecular diagnosis of MS. Reproductive evaluation confirmed a normosmic idiopathic hypogonadotropic hypogonadism. Review of the RAB3GAP2 allelic spectrum in WARBM/MS suggests that although variants resulting in complete abrogation of RAB3GAP2 protein function cause severe WARBM, variants associated with partially preserved RAB3GAP2 function cause milder MS. This report expands the genotypic and phenotypic spectrum of MS and demonstrates hypogonadotropic hypogonadism as a key pathophysiologic abnormality in MS. Genotype-phenotype associations of previously reported RAB3GAP2 variants indicate that variants that fully abolish RAB3GAP2 function result in WARBM, whereas MS is associated with variants of lesser severity with residual RAB3GAP2 function.

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Section: Discussionsupporting

confidence: 89%

Hypogonadotropic hypogonadism due to variants in RAB3GAP2: expanding the phenotypic and genotypic spectrum of Martsolf syndrome

Plummer

Quinton

et al. 2020

Cold Spring Harb Mol Case Stud

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“…Our findings provide a clinical impetus to now develop and test functional hypotheses regarding disease mechanism(s). The Dmxl2 gene is best studied in the gonadotropin-releasing hormone neurons [42, 67], where low expression in mice impedes normal dendritic development [67]. However, the phenotypes observed in knockout mice are not entirely attributable to deficient Dmxl2 in that neuronal cell population [67].…”

Section: Discussionmentioning

confidence: 99%

“…The Dmxl2 gene is best studied in the gonadotropin-releasing hormone neurons [42, 67], where low expression in mice impedes normal dendritic development [67]. However, the phenotypes observed in knockout mice are not entirely attributable to deficient Dmxl2 in that neuronal cell population [67]. Dmxl2 +/− mice also demonstrate neuroanatomical differences in the corpus callosum [68].…”

Section: Discussionmentioning

confidence: 99%

Rare copy number variations affecting the synaptic gene DMXL2 in neurodevelopmental disorders

Costain

Walker

Argiropoulos

et al. 2019

J Neurodevelop Disord

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BackgroundUltra-rare genetic variants, including non-recurrent copy number variations (CNVs) affecting important dosage-sensitive genes, are important contributors to the etiology of neurodevelopmental disorders (NDDs). Pairing family-based whole-genome sequencing (WGS) with detailed phenotype data can enable novel gene associations in NDDs.MethodsWe performed WGS of six members from a three-generation family, where three individuals each had a spectrum of features suggestive of a NDD. CNVs and sequence-level variants were identified and further investigated in disease and control databases.ResultsWe identified a novel 252-kb deletion at 15q21 that overlaps the synaptic gene DMXL2 and the gene GLDN. The microdeletion segregated in NDD-affected individuals. Additional rare inherited and de novo sequence-level variants were found that may also be involved, including a missense change in GRIK5. Multiple CNVs and loss-of-function sequence variants affecting DMXL2 were discovered in additional unrelated individuals with a range of NDDs.ConclusionsDisruption of DMXL2 may predispose to NDDs including autism spectrum disorder. The robust interpretation of private variants requires a multifaceted approach that incorporates multigenerational pedigrees and genome-wide and population-scale data.

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“…Notably, the potential contribution of ASPHD1 to reproductive function via a putative role in synaptic vesicle integrity is consistent with the biological roles of some Mendelian GnRH deficiency disorder genes. For example, recessive mutations in DMXL2, encoding the synaptic vesicle protein rabconnectin-3α, cause delayed puberty due to a reduction of GnRH neurons in the hypothalamus and attenuated kisspeptin responsiveness [71,72].…”

Section: Discussionmentioning

confidence: 99%

Leveraging biobank-scale rare and common variant analyses to identify ASPHD1 as the main driver of reproductive traits in the 16p11.2 locus

Männik

Arbogast

Lepamets

et al. 2019

Preprint

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Whereas genome-wide association studies (GWAS) allowed identifying thousands of associations between variants and traits, their success rate in pinpointing causal genes has been disproportionately low. Here, we integrate biobank-scale phenotype data from carriers of a rare copy-number variant (CNV), Mendelian randomization and animal modeling to identify causative genes in a GWAS locus for age at menarche (AaM). We show that the dosage of the 16p11.2 BP4-BP5 interval is correlated positively with AaM in the UK and Estonian biobanks and 16p11.2 clinical cohorts, with a directionally consistent trend for pubertal onset in males. These correlations parallel an increase in reproductive tract disorders in both sexes. In support of these observations, 16p11.2 mouse models display perturbed pubertal onset and structurally altered reproductive organs that track with CNV dose. Further, we report a negative correlation between the 16p11.2 dosage and relative hypothalamic volume in both humans and mice, intimating a perturbation in the gonadotropin-releasing hormone (GnRH) axis. Two independent lines of evidence identified candidate causal genes for AaM; Mendelian randomization and agnostic dosage modulation of each 16p11.2 gene in zebrafish gnrh3:egfp models. ASPHD1, expressed predominantly in brain and pituitary gland, emerged as a major phenotype driver; and it is subject to modulation by KCTD13 to exacerbate GnRH neuron phenotype. Together, our data highlight the power of an interdisciplinary approach to elucidate disease etiologies underlying complex traits.

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Rabconnectin-3α is required for the morphological maturation of GnRH neurons and kisspeptin responsiveness

Cited by 16 publications

References 41 publications

Hypogonadotropic hypogonadism due to variants in RAB3GAP2: expanding the phenotypic and genotypic spectrum of Martsolf syndrome

Hypogonadotropic hypogonadism due to variants in RAB3GAP2: expanding the phenotypic and genotypic spectrum of Martsolf syndrome

Rare copy number variations affecting the synaptic gene DMXL2 in neurodevelopmental disorders

Leveraging biobank-scale rare and common variant analyses to identify ASPHD1 as the main driver of reproductive traits in the 16p11.2 locus

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