[Encopresis in children, the view of child psychiatry]. / Comment j'explore... L'encoprésie chez l'enfant, le point de vue pédopsychiatrique.

The article aims to provide a state of knowledge in the literature on encopresis in the child psychiatric population. The general definition of the symptom and its analysis are presented according to different approaches. Then, the clinic of encopresis is described according to its specificities. The main associated disorders and psychiatric/psychosocial risk factors are discussed in detail. Regarding patient care, the multidisciplinary approach, including the complementarity with the paediatrician, is essential in a number of cases. Finally, family approach and the impact of trauma would be interesting research perspectives.

L'article a pour objectif de proposer un état des connaissances dans la littérature au sujet de l'encoprésie parmi la population pédopsychiatrique. La définition générale du symptôme et son analyse sont exposées selon différentes approches. Ensuite, la clinique de l'encoprésie est abordée selon ses spécificités. Les principaux troubles associés et les facteurs de risques psychiatriques/psychosociaux sont alors abordés dans le détail. Au niveau de la prise en charge du patient, l'approche multidisciplinaire, dont la complémentarité avec le pédiatre, est primordiale dans un certain nombre de cas. Enfin, l'approche familiale et l'impact des traumatismes constitueraient des perspectives de recherche intéressantes.

Functional analysis of Peutz-Jeghers mutations reveals that the LKB1 C-terminal region exerts a crucial role in regulating both the AMPK pathway and the cell polarity.

Germline mutations of the LKB1 gene are responsible for the cancer-prone Peutz-Jeghers syndrome (PJS). LKB1 encodes a serine-threonine kinase that acts as a regulator of cell cycle, metabolism and cell polarity. The majority of PJS missense mutations abolish LKB1 enzymatic activity and thereby impair all functions assigned to LKB1. Here, we have investigated the functional consequences of recurrent missense mutations identified in PJS and in sporadic tumors which map in the LKB1 C-terminal non-catalytic region. We report that these C-terminal mutations neither disrupt LKB1 kinase activity nor interfere with LKB1-induced growth arrest. However, these naturally occuring mutations lessened LKB1-mediated activation of the AMP-activated protein kinase (AMPK) and impaired downstream signaling. Furthermore, C-terminal mutations compromise LKB1 ability to establish and maintain polarity of both intestinal epithelial cells and migrating astrocytes. Consistent with these findings, mutational analysis reveals that the LKB1 tail exerts an essential function in the control of cell polarity. Overall, our results ascribe a crucial regulatory role to the LKB1 C-terminal region. Our findings further indicate that LKB1 tumor suppressor activity is likely to depend on the regulation of AMPK signaling and cell polarization.

Stability of the Peutz-Jeghers syndrome kinase LKB1 requires its binding to the molecular chaperones Hsp90/Cdc37.

Peutz-Jeghers syndrome (PJS) is an autosomal dominant disorder characterized by the presence of multiple gastrointestinal polyps and an increased risk for various types of cancers. Inactivating germline mutations of the LKB1 gene, which encodes a serine/threonine kinase, are responsible for the majority of PJS cases. Here, we show that the heteromeric complex containing the molecular chaperones Hsp90 and Cdc37/p50 interacts with the kinase domain of LKB1. Treatment of cells with either geldanamycin or novobiocin, two pharmacological inhibitors of Hsp90 causes the destabilization of LKB1. Furthermore, geldanamycin treatment leads to the ubiquitination and the rapid degradation of LKB1 by the proteasome-dependent pathway. In addition, we found that a LKB1 point mutation identified in a sporadic testicular cancer, weakens the interaction of LKB1 with both Hsp90 and Cdc37/p50 and enhances its sensitivity to the destabilizing effect of geldanamycin. Collectively, our results demonstrate that the Hsp90/Cdc37 complex is a major regulator of the stability of the LKB1 tumor suppressor. Furthermore, these data draw attention to the possible adverse consequences of antitumor drugs that target Hsp90, such as antibiotics related to geldanamycin, which could disrupt LKB1 function and promote the development of polyps and carcinomatous lesions.