3 research outputs found
Diabetic Dead-in-Bed Syndrome: A Possible Link to a Cardiac Ion Channelopathy
Sudden unexpected nocturnal death among patients with diabetes occurs approximately ten times more commonly than in the general population. Malignant ventricular arrhythmia due to Brugada syndrome has been postulated as a cause, since a glucose-insulin bolus can unmask the Brugada electrocardiographic signature in genetically predisposed individuals. In this report we present a 16-year-old male with insulin-dependent diabetes who died suddenly at night. His diabetes had been well controlled, without significant hypoglycaemia. At autopsy, he had a full stomach and a glucose level of 7 mmol/L in vitreous humor, excluding hypoglycaemia. Genetic analysis of autopsy DNA revealed a missense mutation, c.370A>G (p.Ile124Val), in the GPD1L gene. A parent carried the same mutation and has QT prolongation. Mutations in this gene have been linked to Brugada syndrome and sudden infant death. The patient may have died from a ventricular arrhythmia, secondary to occult Brugada syndrome, triggered by a full stomach and insulin. The data suggest that molecular autopsies are warranted to investigate other cases of the diabetic dead-in-bed syndrome
TOPAZ1, a Novel Germ Cell-Specific Expressed Gene Conserved during Evolution across Vertebrates
BACKGROUND: We had previously reported that the Suppression Subtractive Hybridization (SSH) approach was relevant for the isolation of new mammalian genes involved in oogenesis and early follicle development. Some of these transcripts might be potential new oocyte and granulosa cell markers. We have now characterized one of them, named TOPAZ1 for the Testis and Ovary-specific PAZ domain gene. PRINCIPAL FINDINGS: Sheep and mouse TOPAZ1 mRNA have 4,803 bp and 4,962 bp open reading frames (20 exons), respectively, and encode putative TOPAZ1 proteins containing 1,600 and 1653 amino acids. They possess PAZ and CCCH domains. In sheep, TOPAZ1 mRNA is preferentially expressed in females during fetal life with a peak during prophase I of meiosis, and in males during adulthood. In the mouse, Topaz1 is a germ cell-specific gene. TOPAZ1 protein is highly conserved in vertebrates and specifically expressed in mouse and sheep gonads. It is localized in the cytoplasm of germ cells from the sheep fetal ovary and mouse adult testis. CONCLUSIONS: We have identified a novel PAZ-domain protein that is abundantly expressed in the gonads during germ cell meiosis. The expression pattern of TOPAZ1, and its high degree of conservation, suggests that it may play an important role in germ cell development. Further characterization of TOPAZ1 may elucidate the mechanisms involved in gametogenesis, and particularly in the RNA silencing process in the germ lin
The Topaz1 gene is necessary for spermatogenesis
Cette thèse décrit pour la première fois le rôle indispensable du gène Topaz1 pour une spermatogenèse correcte chez la souris. Ce gène est spécifique des cellules germinales et possède deux domaines conservés: CCCH et PAZ. Afin d'étudier le rôle de Topaz1, nous avons généré un modèle murin dépourvu de ce gène. Les mâles Topaz1-/- sont stériles dû à un arrêt de la spermatogenèse lors de la première division méiotique. Le poids des testicules mutants est diminué après la première vague de la spermatogenèse comparé à des testicules normaux. Histologique, les différences entre testicules Topaz1-/- et +/+ apparaissent entre 15 et 20 jours après la naissance. Cette déficience en TOPAZ1 induit une absence de cellules germinales haploïdes et une augmentation de l’apoptose, suggérant un arrêt de la spermatogenèse au cours de la première division de méiose. Cet arrêt n’est pas dû à un défaut de formation du complexe synaptonémal ni à une dérégulation de l’inactivation transcriptionnelle des chromosomes sexuels. De plus, malgré la présence d'un domaine PAZ dans la protéine TOPAZ1, son absence n'induit pas une dé-répression des rétrotransposons. Les testicules de ces souris Topaz1-/-, comparés à des animaux normaux, présentent des transcriptomes perturbés avec notamment la dérégulation de l'expression de plusieurs gènes inconnus et d'ARNs non codants longs. Cette étude a permis de démontrer que TOPAZ1 est indispensable à la spermatogenèse de souris. En plus d’être un bon gène candidat pour des cas d’infertilités azoospermiques non obstructives chez l’Homme, Topaz1 pourrait ouvrir des nouveaux champs d'investigations impliquant de nouvelles voies de régulation de la spermatogenèse.This thesis describes for the first time the crucial role in spermatogenesis of the Topaz1gene in mice. This gene is germ cells-specific and contains two conserved domains: CCCH and PAZ. In order to study the role of Topaz1, our laboratory has generated a mouse model deleted for this gene. Topaz1-/- males are infertile because of an arrest of spermatogenesis during the first meiotic division. Mutant’s testicular weight is reduced after the first wave of spermatogenesis, compared with normal testis. Histologically, differences between Topaz1-/- and +/+ testes appear between 15 and 20 days after birth. Deletion of Topaz1 causes a lack of haploid germ cells and an increase of apoptosis, suggesting an interruption of spermatogenesis during the first meiotic division. This meiotic arrest is not caused nor by a synaptonemal complex formation defect nor by a misregulation of the MSCI (Meiotic Sex Chromosomes Inactivation). Despite the PAZ domain contained in the TOPAZ1 protein, its invalidation does not activate retrotransposon expression. Topaz1-null testes reveal disturbed transcriptomes with a misregulation of several unknown genes and long non-coding RNAs expression. These results suggest a new regulation pathway of spermatogenesis, parallel and independent to the piRNAs pathway. This new pathway could implicate lncRNAs regulations. This study demonstrated the essential role of Topaz1in mice spermatogenesis. This gene is a good candidate for azoospermia non-obstructive infertility in men. Topaz1 could open new fields of investigation involving spermatogenesis new regulation pathways