Haploinsufficiency of Dmxl2, Encoding a Synaptic Protein, Causes Infertility Associated with a Loss of GnRH Neurons in Mouse

International audienceCharacterization of the genetic defects causing gonadotropic deficiency has made a major contribution to elucidation of the fundamental role of Kisspeptins and Neurokinin B in puberty onset and reproduction. The absence of puberty may also reveal neurodevelopmental disorders caused by molecular defects in various cellular pathways. Investigations of these neurodevelopmental disorders may provide information about the neuronal processes controlling puberty onset and reproductive capacity. We describe here a new syndrome observed in three brothers, which involves gonadotropic axis deficiency, central hypothyroidism, peripheral demyelinating sensorimotor polyneuropathy, mental retardation, and profound hypoglycemia, progressing to nonautoimmune insulin-dependent diabetes mellitus. High-throughput sequencing revealed a homozygous in-frame deletion of 15 nucleotides in DMXL2 in all three affected patients. This homozygous deletion was associated with lower DMXL2 mRNA levels in the blood lymphocytes of the patients. DMXL2 encodes the synaptic protein rabconnectin-3a, which has been identified as a putative scaffold protein for Rab3-GAP and Rab3-GEP, two regulators of the GTPase Rab3a. We found that rabconnectin-3a was expressed in exocytosis vesicles in gonadotropin-releasing hormone (GnRH) axonal extremities in the median eminence of the hypothalamus. It was also specifically expressed in cells expressing luteinizing hormone (LH) and follicle-stimulating hormone (FSH) within the pituitary. The conditional heterozygous deletion of Dmxl2 from mouse neurons delayed puberty and resulted in very low fertility. This reproductive phenotype was associated with a lower number of GnRH neurons in the hypothalamus of adult mice. Finally, Dmxl2 knockdown in an insulin-secreting cell line showed that rabconnectin-3a controlled the constitutive and glucose-induced secretion of insulin. In conclusion, this study shows that low levels of DMXL2 expression cause a complex neurological phenotype, with abnormal glucose metabolism and gonadotropic axis deficiency due to a loss of GnRH neurons. Our findings identify rabconectin-3a as a key controller of neuronal and endocrine homeostatic processes

Safety Outcomes and Near-Adult Height Gain of Growth Hormone-Treated Children with SHOX Deficiency: Data from an Observational Study and a Clinical Trial

Background/Aims: To assess auxological and safety data for growth hormone (GH)-Treated children with SHOX deficiency. Methods: Data were examined for GH-Treated SHOX-deficient children (n = 521) from the observational Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS). For patients with near-Adult height information, GeNeSIS results (n = 90) were compared with a clinical trial (n = 28) of SHOX-deficient patients. Near-Adult height was expressed as standard deviation score (SDS) for chronological age, potentially increasing the observed effect of treatment. Results: Most SHOX-deficient patients in GeNeSIS had diagnoses of Leri-Weill syndrome (n = 292) or non-syndromic short stature (n = 228). For GeNeSIS patients with near-Adult height data, mean age at GH treatment start was 11.0 years, treatment duration 4.4 years, and height SDS gain 0.83 (95% confidence interval 0.49-1.17). Respective ages, GH treatment durations and height SDS gains for GeNeSIS patients prepubertal at baseline (n = 42) were 9.2 years, 6.0 years and 1.19 (0.76-1.62), and for the clinical trial cohort they were 9.2 years, 6.0 years and 1.25 (0.92-1.58). No new GH-related safety concerns were identified. Conclusion: Patients with SHOX deficiency who had started GH treatment before puberty in routine clinical practice had a similar height gain to that of patients in the clinical trial on which approval for the indication was based, with no new safety concerns

Mitchell-Riley Syndrome : Improving Clinical Outcomes and Searching for Functional Impact of RFX-6 Mutations

Aims/HypothesisCaused by biallelic mutations of the gene encoding the transcription factor RFX6, the rare Mitchell-Riley syndrome (MRS) comprises neonatal diabetes, pancreatic hypoplasia, gallbladder agenesis or hypoplasia, duodenal atresia, and severe chronic diarrhea. So far, sixteen cases have been reported, all with a poor prognosis. This study discusses the multidisciplinary intensive clinical management of 4 new cases of MRS that survived over the first 2 years of life. Moreover, it demonstrates how the mutations impair the RFX6 function. MethodsClinical records were analyzed and described in detail. The functional impact of two RFX6(R181W) and RFX6(V506G) variants was assessed by measuring their ability to transactivate insulin transcription and genes that encode the L-type calcium channels required for normal pancreatic beta-cell function. ResultsAll four patients were small for gestational age (SGA) and prenatally diagnosed with duodenal atresia. They presented with neonatal diabetes early in life and were treated with intravenous insulin therapy before switching to subcutaneous insulin pump therapy. All patients faced recurrent hypoglycemic episodes, exacerbated when parenteral nutrition (PN) was disconnected. A sensor-augmented insulin pump therapy with a predictive low-glucose suspension system was installed with good results. One patient had a homozygous c.1517T>G (p.Val506Gly) mutation, two patients had a homozygous p.Arg181Trp mutation, and one patient presented with new compound heterozygosity. The RFX6(V506G) and RFX6(R181W) mutations failed to transactivate the expression of insulin and genes that encode L-type calcium channel subunits required for normal pancreatic beta-cell function. Conclusions/InterpretationMultidisciplinary and intensive disease management improved the clinical outcomes in four patients with MRS, including adjustment of parenteral/oral nutrition progression and advanced diabetes technologies. A better understanding of RFX6 function, in both intestine and pancreas cells, may break ground in new therapies, particularly regarding the use of drugs that modulate the enteroendocrine system.Peer reviewe

Morphologies

Séminaire commun avec la participation de : Olivier Abel, Luciano Boi, Jean-Claude Bonne, Marion Carel, Giovanni Careri, Enrico Castelli Gattinara, Patrice Ceccarini, Danièle Cohn, Georges Didi-Huberman, Fernando Gil, Maurizio Gribaudi, Ryozo Hiyama, Bernard Jaulin, Gérard Jorland, Farhad Khosrokhavar, Hervé Le Bras, Giovanni Levi, Sabina Loriga, Silvia Mancini, Jean Petitot, Pierre Rosenstiehl, Carlo Severi, Wiktor Stoczkowski, Lorraine Verner Compte rendu non communiqué

Morphologies

Séminaire commun avec la participation de : Olivier Abel, Luciano Boi, Jean-Claude Bonne, Marion Carel, Giovanni Careri, Enrico Castelli Gattinara, Patrice Ceccarini, Ryozo Hiyama, Georges Didi-Huberman, Maurizio Gribaudi, Bernard Jaulin, Gérard Jorland, Farhad Khosrokhavar, Hervé Le Bras, Giovanni Levi, Sabina Loriga, Silvia Mancini, Zacarías Moutoukias, Jean Petitot, Pierre Rosenstiehl, Carlo Severi, Irène Tamba, Lorraine Verner, Wiktor Stoczkowski Compte rendu non communiqué

Morphologies

Séminaire commun avec la participation d’Olivier Abel, Luciano Boi, Jean-Claude Bonne, Marion Carel, Giovanni Careri, Enrico Castelli Gattinara, Patrice Ceccarini, Danièle Cohn, Ryozo Hiyama, Georges Didi-Huberman, Fernando Gil, Maurizio Gribaudi, Bernard Jaulin, Farhad Khosrokhavar, Hervé Le Bras, Giovanni Levi, Sabina Loriga, Silvia Mancini, Zacarias Moutoukias, Jean Petitot, Pierre Rosenstiehl, Carlo Severi, Lorraine Verner, Wiktor Stoczkowski Voici, les différents sujets abordés et discut..

Pathogenic variants in the DEAH-box RNA helicase DHX37 are a frequent cause of 46,XY gonadal dysgenesis and 46,XY testicular regression syndrome

XY individuals with disorders/differences of sex development (DSD) are characterized by reduced androgenization caused, in some children, by gonadal dysgenesis or testis regression during fetal development. The genetic etiology for most patients with 46,XY gonadal dysgenesis and for all patients with testicular regression syndrome (TRS) is unknown

Cancer risks in patients treated with growth hormone in childhood: the SAGhE European cohort study.

Context: Growth hormone (GH) is prescribed for an increasing range of indications, but there has been concern that it might raise cancer risk. Published data are limited. Objective: To examine cancer risks in relation to GH treatment. Design: Cohort study. Setting: Population-based. Patients: Cohort of 23,984 patients treated with recombinant human GH (r-hGH) in eight European countries since this treatment was first used in 1984. Cancer expectations from country-specific national population statistics. Main Outcome Measures: Cancer incidence and cancer mortality. Results: Incidence and mortality risks in the cohort were raised for several cancer sites, largely consequent on second primary malignancies in patients given r-hGH after cancer treatment. There was no clear raised risk in patients with growth failure without other major disease. Only for bone and bladder cancers was incidence significantly raised in GH-treated patients without previous cancer. Cancer risk was unrelated to duration or cumulative dose of r-hGH treatment, but for patients treated after previous cancer, cancer mortality risk increased significantly with increasing daily r-hGH dose (P trend < 0.001). Hodgkin lymphoma (HL) incidence increased significantly with longer follow-up (P trend = 0.001 for patients overall and 0.002 for patients without previous cancer). Conclusions: Our results do not generally support a carcinogenic effect of r-hGH, but the unexplained trend in cancer mortality risk in relation to GH dose in patients with previous cancer, and the indication of possible effects on bone cancer, bladder cancer, and HL risks, need further investigation

Rare and low-frequency coding variants alter human adult height

Height is a highly heritable, classic polygenic trait with ~700 common associated variants identified so far through genome - wide association studies . Here , we report 83 height - associated coding variants with lower minor allele frequenc ies ( range of 0.1 - 4.8% ) and effects of up to 2 16 cm /allele ( e.g. in IHH , STC2 , AR and CRISPLD2 ) , >10 times the average effect of common variants . In functional follow - up studies, rare height - increasing alleles of STC2 (+1 - 2 cm/allele) compromise d proteolytic inhibition of PAPP - A and increased cleavage of IGFBP - 4 in vitro , resulting in higher bioavailability of insulin - like growth factors . The se 83 height - associated variants overlap genes mutated in monogenic growth disorders and highlight new biological candidates ( e.g. ADAMTS3, IL11RA, NOX4 ) and pathways ( e.g . proteoglycan/ glycosaminoglycan synthesis ) involved in growth . Our results demonstrate that sufficiently large sample sizes can uncover rare and low - frequency variants of moderate to large effect associated with polygenic human phenotypes , and that these variants implicate relevant genes and pathways

How safe is growth hormone therapy? SAGhE and beyond

International audienc