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

Abstract

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 &lt;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.

Genomic Diversity and Selection Signatures for Weining Cattle on the Border of Yunnan-Guizhou

“…After overlapping these two gene clusters, 203 genes were analyzed ( Supplementary Figure S1C ). Of these genes, DLG2 , PRLR , MLH1 , CFAP299 , GOLGA4, and CCNH were reported as reproductive trait–related candidate genes ( Ortega et al, 2016 ; Li H. et al, 2019 ; Singh et al, 2019 ; Sweett et al, 2020 ; Shi et al, 2021 ; Turan et al, 2021 ). The age of first mating of Weining cattle is 22 months, which is 3–5 months later than that of Wannan cattle and Wenshan cattle ( China National Commission of Animal Genetic Resources, 2011 ).…”

<b><i>SLIT2</i></b> Rare Sequencing Variants Identified in Idiopathic Hypogonadotropic Hypogonadism

“…Whole-exome sequencing in IHH probands and ethnic-matched controls was performed as previously described [26, 27]. We have screened for rare sequencing variants (RSVs, minor allele frequency <1% in the Genome Aggregation Database) in SLIT2 as well as 57 known IHH-associated genes [10].…”

“…IHH has a high degree of genetic heterogeneity. Variants were described in more than 50 genes [1, 3, 9, 10]. Unbiased genetic methodologies were used to discover several genes.…”

A mild impairment in reversal learning in a bowl‐digging substrate deterministic task but not other cognitive tests in the Dlg2+/− rat model of genetic risk for psychiatric disorder

“…Genetic variation in the Dlg2 gene, which encodes the membrane associated guanylate kinase (MAGUK) synaptic scaffolding protein PSD93, also known as Dlg2 or chapsyn‐110, has been associated with an array of psychiatric disorders 1 including schizophrenia, 2 intellectual disability, 3 bipolar disorder, 4 autism spectrum disorder, 5 attention deficit hyperactivity disorder, 6 and pubertal disorders. 7 , 8 The PSD93 protein is expressed widely throughout the brain 9 , 10 , 11 and has been demonstrated to interact with a variety of other proteins in the postsynaptic density, including NMDAR receptor subunits, 12 , 13 , 14 , 15 , 16 AMPAR auxiliary subunit stargazin, 17 potassium channels, 18 , 19 , 20 , 21 and other cytoskeletal components. 12 , 22 , 23 , 24 , 25 , 26 Work on homozygous knockout rodents models of Dlg2−/− has found evidence of deficits in glutamatergic signalling, 10 , 14 , 27 , 28 , 29 , 30 , 31 plasticity, 28 and dendritic 32 and spine 31 morphology in the hippocampus, dorsal striatum, spinal dorsal horn, and cingular and visual cortices.…”

“…Genetic variation in the Dlg2 gene, which encodes the membrane associated guanylate kinase (MAGUK) synaptic scaffolding protein PSD93, also known as Dlg2 or chapsyn‐110, has been associated with an array of psychiatric disorders 1 including schizophrenia, 2 intellectual disability, 3 bipolar disorder, 4 autism spectrum disorder, 5 attention deficit hyperactivity disorder, 6 and pubertal disorders 7,8 . The PSD93 protein is expressed widely throughout the brain 9–11 and has been demonstrated to interact with a variety of other proteins in the postsynaptic density, including NMDAR receptor subunits, 12–16 AMPAR auxiliary subunit stargazin, 17 potassium channels, 18–21 and other cytoskeletal components 12,22–26 .…”