👤 Andrea Messina

What is the clinical and genetic overlap across subtypes of congenital gonadotropin (Gn) deficiency? This study reveals substantial clinical and genetic overlap among Gn deficiency disorders, with shared genetic and developmental features across congenital hypogonadotropic hypogonadism (CHH), combined pituitary hormone deficiency (CPHD), and syndromic forms of Gn deficiency. Congenital Gn deficiency includes a subset of hypogonadotropic hypogonadism (HH) and can result from defects at the level of the hypothalamus or the pituitary. It includes (i) CHH, further classified into normosmic CHH (nCHH) and Kallmann syndrome (KS); (ii) CPHD; and (iii) syndromic forms such as CHARGE syndrome and septo-optic dysplasia (SOD). The study included all probands with Gn deficiency recruited at a tertiary care center between 2011 and 2024 (n = 568), including 276 KS, 247 nCHH, 29 CPHD, and 16 syndromic Gn deficiency cases. All individuals underwent detailed clinical phenotyping followed by DNA sequencing. Genetic analysis focused on pathogenic (P) and likely pathogenic (LP) variants and variants of uncertain significance (VUS) within established CHH and CPHD genes. Oligogenicity was assessed in the CHH/syndromic HH cohort (n = 523) compared with controls from 1000 Genomes (n = 601). Genetic overlap among CHH, CPHD, and syndromic Gn deficiency was systematically investigated. Cleft lip/palate, dental agenesis, and ear abnormalities were recurrent across all Gn-deficient groups. Notably, some CPHD and SOD patients exhibited anosmia and a preserved Gn response to LH-releasing hormone (LHRH) stimulation, indicating a hypothalamic component to their HH. Rare variants in CHH genes were identified in 53% of KS probands (40% P/LP, 13% VUS) and 33% of nCHH probands (23% P/LP, 10% VUS). N/A. Non-coding and copy number variants were not studied. Functional studies of the new candidate genes for CHH were not undertaken. This study highlights the importance of comprehensive clinical evaluation and broadened genetic testing in patients with Gn deficiency. This work was supported by the Swiss National Foundation (NP) (Grant No. 310030B₂₀₁₂₇₅ to N.P.) and the Natural Science Foundation of Beijing (Grant No. 7244338 to Y.W.). The authors declare no competing interests. Show less

Congenital hypogonadotropic hypogonadism (CHH) is a rare and genetically heterogeneous disorder characterized by absent or incomplete puberty due to impaired gonadotropin-releasing hormone (GnRH) function. A subset of individuals with CHH also present with developmental anomalies, including midline defects such as cleft lip and/or palate (CLP). This study investigates the genetic overlap between CHH and CLP. A total of 336 individuals diagnosed with CHH were clinically assessed for associated phenotypes, including CLP. High-throughput sequencing was performed using a targeted gene panel encompassing known CHH- and CLP-related genes. Variants were analyzed and classified according to the American College of Medical Genetics and Genomics (ACMG) criteria for pathogenicity. CLP was present in 21 patients with CHH (6%). Pathogenic or likely pathogenic variants in genes associated with both CHH and CLP-such as FGFR1 and CHD7-were identified in eight individuals. Furthermore, 17% of the patients with CHH without CLP harbored deleterious variants in genes implicated in clefting, including DVL3, PLCB4, NIPBL, and EDNRA. Evidence of digenic inheritance involving both CHH- and CLP-related genes was observed in multiple cases. FGFR1 variants were the most frequently detected and were commonly associated with anosmia and additional developmental anomalies. These findings highlight a genetic and phenotypic continuum between CHH and CLP, underscoring the involvement of shared developmental pathways. The high prevalence of FGFR1 variants in patients with CHH and CLP supports its role as a pleiotropic gene. Understanding the overlapping genetic mechanisms may enhance diagnostic precision and inform personalized management strategies for affected individuals. Show less

Glioblastoma (GBM) is the most aggressive and common form of primary brain cancer. Survival is poor and improved treatment options are urgently needed. Dual specificity phosphatase-6 (DUSP6) is actively involved in oncogenesis showing unexpected tumor-promoting properties in human glioblastoma, contributing to the development and expression of the full malignant and invasive phenotype. The purpose of this study was to assess if DUSP6 activates epithelial-to-mesenchymal transition (EMT) in glioblastoma and its connection with the invasive capacity. We found high levels of transcripts mRNA by qPCR analysis in a panel of primary GBM compared to adult or fetal normal tissues. At translational levels, these data correlate with high protein expression and long half-life values by cycloheximide-chase assay in immunoblot experiments. Next, we demonstrate that DUSP6 gene is involved in epithelial-to-mesenchymal transition (EMT) in GBM by immunoblot characterization of the mesenchymal and epithelial markers. Vimentin, N-Cadherin, E-Cadherin and fibronectin were measured with and without DUSP6 over-expression, and in response to several stimuli such as chemotherapy treatment. In particular, the high levels of vimentin were blunted at increasing doses of cisplatin in condition of DUSP6 over-expression while N-Cadherin contextually increased. Finally, DUSP6 per se increased invasion capacity of GBM. Overall, our data unveil the DUSP6 involvement in invasive mesenchymal-like properties in GBM. Show less

Dual-specificity phosphatase 6 (DUSP6, mitogen-activated protein kinase (MAPK) phosphatase 3 or PYST1) dephosphorylates phosphotyrosine and phosphothreonine residues on extracellular signal-regulated kinase (ERK1/2; MAPK1/2) to inactivate the ERK1/2 kinase. DUSP6 is a critical regulator of the ERK signaling cascade and has been implicated as a tumor suppressor. We report here experimental evidences that DUSP6 is transcriptionally upregulated in primary and long-term cultures of human glioblastoma, as assayed by northern hybridization and real-time quantitative PCR, producing constitutive high level of protein expression. Functional assays were performed with adenovirus-mediated expression of DUSP6 in glioblastoma cultures. Protein overexpression inhibits growth by inducing G1-phase delay and increased mitogenic/anchorage dependence and clonogenic potential in vitro. Changes in cell morphology were associated with an increased tumor growth in vivo. Chemoresistance is a major cause of treatment failure and poor outcome in human glioblastomas. Importantly, DUSP6 overexpression increased resistance to cisplatin-mediated cell death in vitro and in vivo. Antisense-mediated depletion of DUSP6 acted in lowering the threshold to anticancer DNA-damaging drugs. We conclude that upregulation of DUSP6 exerts a tumor-promoting role in human glioblastomas exacerbating the malignant phenotype. Show less