DLG2 variants in patients with pubertal disorders

Jee, Youn Hee; Won, Sehoon; Lui, Julian C.; Jennings, Melissa; Whalen, Philip; Yue, Shanna; Temnycky, Adrian G.; Barnes, Kevin M.; Cheetham, Tim; Boden, Matthew G.; Radovick, Sally; Quinton, Richard; Leschek, Ellen; Aguilera, Greti; Yanovski, Jack A.; Seminara, Stephanie B.; Crowley, William F.; Delaney, Angela; Roche, Katherine W.; Baron, Jeffrey

doi:10.1038/s41436-020-0803-8

Cited by 9 publications

(11 citation statements)

References 42 publications

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“…Therefore, confirmation of newly described genes in different cohorts has become essential. Recently, heterozygous DLG2 variants were reported to cause delayed puberty and contribute to IHH [2].…”

Section: Discussionmentioning

confidence: 99%

“…Variants were described according to the HGVS nomenclature [8]. The transcript variant NM_001142699.1 was used for DLG2 as in a previous report [2].…”

Section: Methodsmentioning

confidence: 99%

“…Studies have shown that N-methyl-D-aspartate receptors are associated with the timing of sexual maturation in animals [3-7]. DLG2 variants were recently reported to be associated with delayed puberty and may also contribute to IHH [2]. Our aim in the present study was to determine whether there are cases that can be explained by DLG2 variants in a large cohort of IHH patients.…”

Section: Introductionmentioning

confidence: 94%

“…Therefore, the confirmation of the reported genes in independent IHH cohorts has become critical. This field is still fertile for new gene discoveries, and recently another gene was reported to be associated with IHH [2]. DLG2 encodes for PSD-93 which is a binding protein for the activation of N-methyl-D-aspartate receptors.…”

Section: Introductionmentioning

confidence: 99%

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DLG2 Mutations in the Etiology of Pubertal Delay and Idiopathic Hypogonadotropic Hypogonadism

et al. 2021

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Introduction: Idiopathic Hypogonadotropic hypogonadism (IHH) is caused by dysfunction of the hypothalamic-pituitary-gonadal axis. DLG2 was recently implicated as a gene associated with delayed puberty and which may also contribute to IHH. The confirmation of the candidate puberty genes in independent IHH cohorts has become crucial due to the lack proper genotype phenotype segregations in reported pedigrees. Therefore, we aimed to screen DLG2 in patients variants in a large cohort of IHH patients. Methods: The present study included a total of 336 IHH patients from 290 independent families. The coding and flanking regions of the DLG2 were screened for potentially important variants in the WES data. Candidate variants were evaluated in the gnomAD and GME databases according to their allele frequencies, and only those with a frequency <0.0001 were considered rare. Detected variants were classified according to the ACMG/AMP criteria. Results: We found one homozygous and two heterozygous missense variants in three independent pedigrees. Identified variants were found extremely rare or not reported in gnomAD. Two variants were categorized as “uncertain significance” the other one was “likely pathogenic” according to the ACMG criteria. All patients were normosmic, and in two of the three families there were no causal variants in other IHH-related genes. Conclusion: We detected three rare sequencing variants in DLG2 in five patients with IHH or delayed puberty in a large IHH cohort. Our results support the contention that the DLG2 mutations are associated with IHH in human puberty.

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Section: Discussionmentioning

confidence: 99%

“…Variants were described according to the HGVS nomenclature [8]. The transcript variant NM_001142699.1 was used for DLG2 as in a previous report [2].…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

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DLG2 Mutations in the Etiology of Pubertal Delay and Idiopathic Hypogonadotropic Hypogonadism

et al. 2021

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“…Variants in DLG2, which encodes a synaptic anchoring protein for NMDA receptors, have been found to segregate with delayed puberty and were additionally found in three patients presenting normosmic CHH. These variants were shown to downregulate Gnrh1 expression in vitro and Dlg2 expression was found in the MPOA of adult rats, suggesting a possible neuroendocrine role for DLG2 within the GnRH neuron system [240].…”

Section: Additional Genesmentioning

confidence: 98%

The Differential Roles for Neurodevelopmental and Neuroendocrine Genes in Shaping GnRH Neuron Physiology and Deficiency

Oleari

Massa

Cariboni

et al. 2021

IJMS

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Gonadotropin releasing hormone (GnRH) neurons are hypothalamic neuroendocrine cells that control sexual reproduction. During embryonic development, GnRH neurons migrate from the nose to the hypothalamus, where they receive inputs from several afferent neurons, following the axonal scaffold patterned by nasal nerves. Each step of GnRH neuron development depends on the orchestrated action of several molecules exerting specific biological functions. Mutations in genes encoding for these essential molecules may cause Congenital Hypogonadotropic Hypogonadism (CHH), a rare disorder characterized by GnRH deficiency, delayed puberty and infertility. Depending on their action in the GnRH neuronal system, CHH causative genes can be divided into neurodevelopmental and neuroendocrine genes. The CHH genetic complexity, combined with multiple inheritance patterns, results in an extreme phenotypic variability of CHH patients. In this review, we aim at providing a comprehensive and updated description of the genes thus far associated with CHH, by dissecting their biological relevance in the GnRH system and their functional relevance underlying CHH pathogenesis.

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Exonic mutations in cell–cell adhesion may contribute to CADASIL-related CSVD pathology

et al. 2023

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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a condition caused by mutations in NOTCH3 and results in a phenotype characterised by recurrent strokes, vascular dementia and migraines. Whilst a genetic basis for the disease is known, the molecular mechanisms underpinning the pathology of CADASIL are still yet to be determined. Studies conducted at the Genomics Research Centre (GRC) have also identified that only 15–23% of individuals clinically suspected of CADASIL have mutations in NOTCH3. Based on this, whole exome sequencing was used to identify novel genetic variants for CADASIL-like cerebral small-vessel disease (CSVD). Analysis of functionally important variants in 50 individuals was investigated using overrepresentation tests in Gene ontology software to identify biological processes that are potentially affected in this group of patients. Further investigation of the genes in these processes was completed using the TRAPD software to identify if there is an increased number (burden) of mutations that are associated with CADASIL-like pathology. Results from this study identified that cell–cell adhesion genes were positively overrepresented in the PANTHER GO-slim database. TRAPD burden testing identified n = 15 genes that had a higher number of rare (MAF < 0.001) and predicted functionally relevant (SIFT < 0.05, PolyPhen > 0.8) mutations compared to the gnomAD v2.1.1 exome control dataset. Furthermore, these results identified ARVCF, GPR17, PTPRS, and CELSR1 as novel candidate genes in CADASIL-related pathology. This study identified a novel process that may be playing a role in the vascular damage related to CADASIL-related CSVD and implicated n = 15 genes in playing a role in the disease.

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DLG2 variants in patients with pubertal disorders

Cited by 9 publications

References 42 publications

<b><i>DLG2</i></b> Mutations in the Etiology of Pubertal Delay and Idiopathic Hypogonadotropic Hypogonadism

<b><i>DLG2</i></b> Mutations in the Etiology of Pubertal Delay and Idiopathic Hypogonadotropic Hypogonadism

The Differential Roles for Neurodevelopmental and Neuroendocrine Genes in Shaping GnRH Neuron Physiology and Deficiency

Exonic mutations in cell–cell adhesion may contribute to CADASIL-related CSVD pathology

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