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IntroductionInterstitial lung disease in children (chILD) are rare and mostly severe lung diseases. Very few epidemiological data are available in limited series of patients. The aim of this study was to assess the prevalence and incidence of chILD in France.MethodsWe performed within the RespiRare network a multicentre retrospective observational study in patients with chILD from 2000 to 2022 and a prospective evaluation of chILD’s incidence between February 2022 and 2023.ResultschILD was reported in 790 patients in 42 centres. The estimated 2022 prevalence in France was 44 /million children (95% CI 40.76 to 47.46) and the computed incidence was 4.4 /million children (95% CI 3.44 to 5.56). The median age at diagnosis was 3 months with 16.9% of familial forms. Lung biopsy and genetic analyses were performed in 23.4% and 76.9%, respectively. The most frequent chILD aetiologies in the <2 years group were surfactant metabolism disorders (16.3%) and neuroendocrine cell hyperplasia of infancy (11.8%), and in the 2–18 years group diffuse alveolar haemorrhage (12.2%), connective tissue diseases (11.4%), hypersensitivity pneumonitis (8.8%) and sarcoidosis (8.8%). The management included mainly oxygen therapy (52%), corticosteroid pulses (56%), oral corticosteroids (44%), azithromycin (27.2%), enteral nutrition (26.9%), immunosuppressants (20.3%) and hydroxychloroquine (15.9%). The 5-year survival rate was 57.3% for the patients diagnosed before 2 years and 86% between 2 and 18 years.ConclusionThis large and systematic epidemiological study confirms a higher incidence and prevalence of chILD than previously described. In order to develop international studies, efforts are still needed to optimise the case collection and to harmonise diagnostic and management practices.

ObjectiveTo identify the characteristics of early life growth associated with later overweight or obesity (OWO) in very preterm population.DesignLength, weight and body mass index (BMI) were prospectively recorded from three prospective, population-based cohorts with 5 years (Loire Infant Follow-up Team (LIFT), EPIPAGE2 (Etude EPIdémiologique sur les Petits Ages GEstationnels 2)) and 15 years (EPIPAGEADO, Etude EPIdémiologique sur les Petits Ages GEstationnels-Adolescents) of follow-up. Missing data were imputed.SettingRegional (LIFT), national (EPIPAGE2) and multiregional (EPIPAGEADO) cohorts in France.PatientsEligible infants born before 33 weeks of gestation in 1997 (EPIPAGEADO), between 2003 and 2014 (LIFT), and in 2011 (EPIPAGE2).Main outcome measuresOWO was determined as BMI Z-score >85th percentile of the WHO reference curves at 5 years (LIFT, EPIPAGE2) and 15 years (EPIPAGEADO).ResultsIn EPIPAGEADO, LIFT and EPIPAGE2, BMI Z-scores were known for 302 adolescents, 1016 children and 2022 children, respectively. In EPIPAGEADO, OWO was observed in 42 (13.9%, 95% CI 10.5 to 18.3) adolescents. In multivariable models, birthweight Z-score, increase in weight Z-score during neonatal hospital stay and increase in BMI between discharge and at 2 years of corrected age were positively associated with OWO at 15 years (adjusted OR (aOR)=3.65, 95% CI 1.36 to 9.76; aOR=3.82, 95% CI 1.42 to 10.3; and aOR=2.55, 95% CI 1.72 to 3.78, respectively, by Z-score), but change in length Z-score during neonatal hospital stay was negatively associated (aOR=0.41, 95% CI 0.21 to 0.78, p=0.007). These four associations with OWO assessed at 5 years were confirmed in the LIFT and EPIPAGE2 cohorts.ConclusionsChange in length Z-score during hospitalisation, a putative proxy of quality of neonatal growth, was negatively associated with risk of later OWO when change in BMI between discharge and at 2 years was included in the multivariable model.

K+deficiency stimulates renal salt reuptake via the Na+-Cl−cotransporter (NCC) of the distal convoluted tubule (DCT), thereby reducing K+losses in downstream nephron segments while increasing NaCl retention and blood pressure. NCC activation is mediated by a kinase cascade involving with no lysine (WNK) kinases upstream of Ste20-related proline-alanine-rich kinase (SPAK) and oxidative stress-responsive kinase-1 (OSR1). In K+deficiency, WNKs and SPAK/OSR1 concentrate in spherical cytoplasmic domains in the DCT termed “WNK bodies,” the significance of which is undetermined. By feeding diets of varying salt and K+content to mice and using genetically engineered mouse lines, we aimed to clarify whether WNK bodies contribute to WNK-SPAK/OSR1-NCC signaling. Phosphorylated SPAK/OSR1 was present both at the apical membrane and in WNK bodies within 12 h of dietary K+deprivation, and it was promptly suppressed by K+loading. In WNK4-deficient mice, however, larger WNK bodies formed, containing unphosphorylated WNK1, SPAK, and OSR1. This suggests that WNK4 is the primary active WNK isoform in WNK bodies and catalyzes SPAK/OSR1 phosphorylation therein. We further examined mice carrying a kidney-specific deletion of the basolateral K+channel-forming protein Kir4.1, which is required for the DCT to sense plasma K+concentration. These mice displayed remnant mosaic expression of Kir4.1 in the DCT, and upon K+deprivation, WNK bodies developed only in Kir4.1-expressing cells. We postulate a model of DCT function in which NCC activity is modulated by plasma K+concentration via WNK4-SPAK/OSR1 interactions within WNK bodies.

Pulmonary alveolar proteinosis (PAP) results from the accumulation of lipoproteinaceous material in the alveoli and alveolar macrophages, and can be associated with pulmonary fibrosis, with a need for lung transplantation (LTx). Causes of PAP are autoimmune (90%-95%), secondary (5%), or hereditary (<1%). Patients with hereditary PAP are generally not considered for isolated LTx, due to the high probability of recurrence after LTx, and only a challenging scenario with sequential LTx followed by hematopoietic stem cell transplantation (HSCT) was reported as successful. Recently, a new genetic cause of PAP linked to mutations in the methionyl-tRNA synthetase (MARS) gene has been reported, with a highly variable clinical presentation. Because clinical correction of the defective MARS activity with methionine supplementation has been reported in nontransplanted children, we reassessed the feasibility of LTx for candidates with MARS-related PAP/fibrosis. We report 3 cases of LTx performed for MARS-related pulmonary alveolar proteinosis–pulmonary fibrosis without recurrence under methionine supplementation, whereas another fourth case transplanted without supplementation had fatal PAP recurrence. These results suggest the effectiveness of methionine in correcting defective MARS activity and also looking for this very rare diagnosis in case of unclassified PAP/fibrosis. It argues for not excluding the feasibility of isolated LTx in patients with MARS mutation.

Renal fibrosis is an important component of chronic kidney disease, an incurable pathology with increasing prevalence worldwide. With a lack of available therapeutic options, end-stage renal disease is currently treated with renal replacement therapy through dialysis or transplantation. In recent years, many efforts have been made to identify novel targets for therapy of renal diseases, with special focus on the characterization of unknown mediators and pathways participating in renal fibrosis development. Using experimental models of renal disease and patient biopsies, we identified four novel mediators of renal fibrosis with potential to constitute future therapeutic targets against kidney disease: discoidin domain receptor 1, periostin, connexin 43, and cannabinoid receptor 1. The four candidates were highly upregulated in different models of renal disease and were localized at the sites of injury. Subsequent studies showed that they are centrally involved in the underlying mechanisms of renal fibrosis progression. Interestingly, inhibition of either of these proteins by different strategies, including gene deletion, antisense administration, or specific blockers, delayed the progression of renal disease and preserved renal structure and function, even when the inhibition started after initiation of the disease. This review will summarize the current findings on these candidates emphasizing on their potential to constitute future targets of therapy:

Familial hyperkalemic hypertension (FHHt) can be mainly attributed to increased activity of the renal Na+:Cl−cotransporter (NCC), which is caused by altered expression and regulation of the with-no-lysine (K) 1 (WNK1) or WNK4 kinases. The WNK1gene gives rise to a kidney-specific isoform that lacks the kinase domain (KS-WNK1), the expression of which occurs primarily in the distal convoluted tubule. The role played by KS-WNK1 in the modulation of the WNK/STE20-proline-alanine rich kinase (SPAK)/NCC pathway remains elusive. In the present study, we assessed the effect of human KS-WNK1 on NCC activity and on the WNK4-SPAK pathway. Microinjection of oocytes with human KS-WNK1 cRNA induces remarkable activation and phosphorylation of SPAK and NCC. The effect of KS-WNK1 was abrogated by eliminating a WNK-WNK-interacting domain and by a specific WNK inhibitor, WNK463, indicating that the activation of SPAK/NCC by KS-WNK1 is due to interaction with another WNK kinase. Under control conditions in oocytes, the activating serine 335 of the WNK4 T loop is not phosphorylated. In contrast, this serine becomes phosphorylated when the intracellular chloride concentration ([Cl−]i) is reduced or when KS-WNK1 is coexpressed with WNK4. KS-WNK1-mediated activation of WNK4 is not due to a decrease of the [Cl−]i. Coimmunoprecipitation analysis revealed that KS-WNK1 and WNK4 interact with each other and that WNK4 becomes autophosphorylated at serine 335 when it is associated with KS-WNK1. Together, these observations suggest that WNK4 becomes active in the presence of KS-WNK1, despite a constant [Cl−]i.

Pseudohypoaldosteronism type II (PHAII) is a genetic disease characterized by association of hyperkalemia, hyperchloremic metabolic acidosis, hypertension, low renin, and high sensitivity to thiazide diuretics. It is caused by mutations in the WNK1, WNK4, KLHL3or CUL3gene. There is strong evidence that excessive sodium chloride reabsorption by the sodium chloride cotransporter NCC in the distal convoluted tubule is involved. WNK4 is expressed not only in distal convoluted tubule cells but also in β−intercalated cells of the cortical collecting duct. These latter cells exchange intracellular bicarbonate for external chloride through pendrin, and therefore, account for renal base excretion. However, these cells can also mediate thiazide-sensitive sodium chloride absorption when the pendrin-dependent apical chloride influx is coupled to apical sodium influx by the sodium-driven chloride/bicarbonate exchanger. Here we determine whether this system is involved in the pathogenesis of PHAII. Renal pendrin activity was markedly increased in a mouse model carrying a WNK4 missense mutation (Q562E) previously identified in patients with PHAII. The upregulation of pendrin led to an increase in thiazide-sensitive sodium chloride absorption by the cortical collecting duct, and it caused metabolic acidosis. The function of apical potassium channels was altered in this model, and hyperkalemia was fully corrected by pendrin genetic ablation. Thus, we demonstrate an important contribution of pendrin in renal regulation of sodium chloride, potassium and acid-base homeostasis and in the pathophysiology of PHAII. Furthermore, we identify renal distal bicarbonate secretion as a novel mechanism of renal tubular acidosis.

With-no-lysine kinase 4 (WNK4) and kidney-specific (KS)-WNK1 regulate ROMK (Kir1.1) channels in a variety of cell models. We now explore the role of WNK4 and KS-WNK1 in regulating ROMK in the native distal convoluted tubule (DCT)/connecting tubule (CNT) by measuring tertiapin-Q (TPNQ; ROMK inhibitor)-sensitive K+currents with whole cell recording. TPNQ-sensitive K+currents in DCT2/CNT of KS-WNK1−/−and WNK4−/−mice were significantly smaller than that of WT mice. In contrast, the basolateral K+channels (a Kir4.1/5.1 heterotetramer) in the DCT were not inhibited. Moreover, WNK4−/−mice were hypokalemic, while KS-WNK1−/−mice had normal plasma K+levels. High K+(HK) intake significantly increased TPNQ-sensitive K+currents in DCT2/CNT of WT and WNK4−/−mice but not in KS-WNK1−/−mice. However, TPNQ-sensitive K+currents in the cortical collecting duct (CCD) were normal not only under control conditions but also significantly increased in response to HK in KS-WNK1−/−mice. This suggests that the deletion of KS-WNK1-induced inhibition of ROMK occurs only in the DCT2/CNT. Renal clearance study further demonstrated that the deletion of KS-WNK1 did not affect the renal ability of K+excretion under control conditions and during increasing K+intake. Also, HK intake did not cause hyperkalemia in KS-WNK1−/−mice. We conclude that KS-WNK1 but not WNK4 is required for HK intake-induced stimulation of ROMK activity in DCT2/CNT. However, KS-WNK1 is not essential for HK-induced stimulation of ROMK in the CCD, and the lack of KS-WNK1 does not affect net renal K+excretion.

Les maladies auto-inflammatoires génétiques sont désormais un groupe de maladies reconnu et en pleine expansion. L’atteinte pulmonaire historiquement associée aux maladies auto-inflammatoires est la sérite inflammatoire, en particulier dans la fièvre méditerranéenne familiale et d’autres pathologies médiées par l’interleukine-1. Depuis une dizaine d’années, l’atteinte pulmonaire est au cœur de la présentation clinique de deux maladies auto-inflammatoires associées à une activation constitutive des interférons de type I, le SAVI et le syndrome COPA. En effet, la plupart des patients atteints de ces pathologies ont une évolution précoce vers la fibrose pulmonaire, responsable d’une morbi-mortalité élevée. D’autres maladies auto-inflammatoires plus rares associent une protéinose alvéolaire, en particulier en association aux mutations de MARS. Enfin, chez l’adulte, le VEXAS est fréquemment associé à une atteinte pulmonaire qui ne semble pas changer le pronostic. La compréhension moléculaire des maladies auto-inflammatoires permet de définir des biomarqueurs pour le diagnostic, mais aussi de proposer des traitements ciblés pour les patients. On peut citer les inhibiteurs de JAK dans le SAVI et le syndrome COPA, bien que ces traitements ne préviennent pas la progression vers la fibrose pulmonaire. Un autre exemple illustratif est l’efficacité de la supplémention en méthionine dans les protéinoses alvéolaires liées aux mutations de MARS. Au total, le poumon apparaît désormais comme un organe qui peut être atteint dans les maladies auto-inflammatoires. Les découvertes croissantes de nouvelles maladies auto-inflammatoires vont probablement révéler d’autres pathologies associant une atteinte pulmonaire. Ces avancées permettront sans doute de développer également de nouvelles perspectives thérapeutiques.

The distal nephron is a heterogeneous part of the nephron composed by six different cell types, forming the epithelium of the distal convoluted (DCT), connecting, and collecting duct. To dissect the function of these cells, knockout models specific for their unique cell marker have been created. However, since this part of the nephron develops at the border between the ureteric bud and the metanephric mesenchyme, the specificity of the single cell markers has been recently questioned. Here, by mapping the fate of the aquaporin 2 (AQP2) and Na+-Cl−cotransporter (NCC)-positive cells using transgenic mouse lines expressing the yellow fluorescent protein fluorescent marker, we showed that the origin of the distal nephron is extremely composite. Indeed, AQP2-expressing precursor results give rise not only to the principal cells, but also to some of the A- and B-type intercalated cells and even to cells of the DCT. On the other hand, some principal cells and B-type intercalated cells can develop from NCC-expressing precursors. In conclusion, these results demonstrate that the origin of different cell types in the distal nephron is not as clearly defined as originally thought. Importantly, they highlight the fact that knocking out a gene encoding for a selective functional marker in the adult does not guarantee cell specificity during the overall kidney development. Tools allowing not only cell-specific but also time-controlled recombination will be useful in this sense.

Chez les enfants prématurés, l’association entre croissance des 1000 premiers jours et surpoids dans l’enfance ou l’adolescence n’est pas claire. L’objectif est d’identifier les caractéristiques fœtales, néonatales et de croissance des 2 premières années associées avec le surpoids ou obésité (SOO) dans une population d’enfants prématurés.

Les mutations du gène SFTPC sont responsables de pathologies interstitielles diffuses et représentent la plus fréquente des pathologies du surfactant chez l’enfant. Notre objectif était de décrire le mode de présentation et l’évolution de la pathologie en fonction du génotype dans une large cohorte de patients porteurs d’une mutation SFTPC.

Prematurity and bronchopulmonary dysplasia (BPD) affect long-term lung function. We studied the respiratory outcome of adolescents born very preterm and controls from the Etude EPIdémiologique sur les Petits Ages Gestationnels cohort and analysed their current lung function in relation to asthma symptoms (categorised in three age groups) from birth. In models including BPD, asthma at each age and confounding factors in the preterm group, BPD and preschool wheeze were the only independent variables associated with FEV1. Preschool wheeze is an independent factor associated with FEV1impairment in adolescents born very preterm. These results highlight the need for optimal management of early respiratory symptoms in preterm-born infants.Trial registration numberResults, NCT01424553.

Unique situations in female physiology require volume retention. Accordingly, a dimorphic regulation of the thiazide-sensitive Na+-Cl−cotransporter (NCC) has been reported, with a higher activity in females than in males. However, little is known about the hormones and mechanisms involved. Here, we present evidence that estrogens, progesterone, and prolactin stimulate NCC expression and phosphorylation. The sex difference in NCC abundance, however, is species dependent. In rats, NCC phosphorylation is higher in females than in males, while in mice both NCC expression and phosphorylation is higher in females, and this is associated with increased expression and phosphorylation of full-length STE-20 proline-alanine-rich kinase (SPAK). Higher expression/phosphorylation of NCC was corroborated in humans by urinary exosome analysis. Ovariectomy in rats resulted in decreased expression and phosphorylation of the cotransporter and promoted the shift of SPAK isoforms toward the short inhibitory variant SPAK2. Conversely, estradiol or progesterone administration to ovariectomized rats restored NCC phosphorylation levels and shifted SPAK expression and phosphorylation towards the full-length isoform. Estradiol administration to male rats induced a significant increase in NCC phosphorylation. NCC is also modulated by prolactin. Administration of this peptide hormone to male rats induced increased phosphorylation of NCC, an effect that was observed even using the ex vivo kidney perfusion strategy. Our results indicate that estradiol, progesterone, and prolactin, the hormones that are involved in sexual cycle, pregnancy and lactation, upregulate the activity of NCC.

Hepatocyte transplantation could be an alternative to liver transplantation for the treatment of metabolic diseases. However, rodent models have shown that engraftment of transplanted cells in the liver is low and requires deposition of cells in hepatic sinusoids. Splanchnic vasodilatators improved hepatocyte engraftment in a rat model. Therefore, we investigated the effect of glyceryl trinitrate (GTN) on the efficacy of cell engraftment and on liver repopulation in the mdr2-knockout mouse, a model for progressive familial intrahepatic cholestasis type 3.

The clinical, biochemical, morphological, and evolutive features of autoimmune hepatitis associated with serum smooth muscle antibodies of anti-actin specificity were retrospectively analyzed in 31 children and adolescents. Cirrhosis was present at diagnosis in all but six patients, including nine of the 12 diagnosed within 6 months from the onset. In 15 children, one or more associated diseases of an immune-mediated mechanism were present, including chronic arthritis, sclerosing cholangitis, inflammatory bowel disease, and cutaneous vasculitis. All patients were treated with prednisone and azathioprine with normalization or improvement of liver function tests: 28 children are currently alive after a mean follow-up of 4 years, 10 months. Treatment was inter rupted in four patients only. Two patients died of liver failure in spite of immunosuppressive therapy before the era of liver transplantation. In spite of prolonged therapy, five other patients ultimately required liver transplantation during adolescence or early adulthood. These results (a) further define a group of autoimmune hepatitis in children characterized by the presence of serum anti-actin antibodies; (b) indicate that immunosuppressive therapy improves liver function, although in most cases it must be continued for a long period to maintain remission; and (c) suggest that progressive liver failure may occur in early adulthood and may require liver transplantation.

The clinical, biochemical, morphological, and evolutive features of autoimmune hepatitis associated with serum smooth muscle antibodies of anti-actin specificity were retrospectively analyzed in 31 children and adolescents. Cirrhosis was present at diagnosis in all but six patients, including nine of the 12 diagnosed within 6 months from the onset. In 15 children, one or more associated diseases of an immune-mediated mechanism were present, including chronic arthritis, sclerosing cholangitis, inflammatory bowel disease, and cutaneous vasculitis. All patients were treated with prednisone and azathioprine with normalization or improvement of liver function tests: 28 children are currently alive after a mean follow-up of 4 years, 10 months. Treatment was inter rupted in four patients only. Two patients died of liver failure in spite of immunosuppressive therapy before the era of liver transplantation. In spite of prolonged therapy, five other patients ultimately required liver transplantation during adolescence or early adulthood. These results (a) further define a group of autoimmune hepatitis in children characterized by the presence of serum anti-actin antibodies; (b) indicate that immunosuppressive therapy improves liver function, although in most cases it must be continued for a long period to maintain remission; and (c) suggest that progressive liver failure may occur in early adulthood and may require liver transplantation.

Pseudohypoaldosteronism type 2 (PHA2) is a rare autosomal dominant form of human arterial hypertension, associated with hyperkalemia and hyperchloremic metabolic acidosis. WNK1and WNK4are two of the genes mutated in PHA2 patients. This review focuses on the mechanisms by which deletions of the first intron of WNK1found in PHA2 patients trigger the disease.

This review aims to describe the recent findings obtained on the regulation of ion transport by microRNAs in physiological and pathological situations in different organs and organisms.

La protéinose alvéolaire pulmonaire liée à des mutations du gène codant l’ARNt synthétase de la méthionine (MARS1) est une maladie rare et grave, d’apparition précoce, qui entraîne le décès avant l’âge de 2 ans chez un tiers des patients. Elle est associée à un défaut d’aminoacylation par cette enzyme, une atteinte hépatique, un retard de croissance et une inflammation systémique. Comme la supplémentation en méthionine dans des modèles de levures mutées restaure une activité enzymatique normale, nous avons étudié l’efficacité d’une telle supplémentation par voie orale chez des patients.

Progressive familial intrahepatic cholestasis (PFIC) and to a lesser extent, Alagille syndrome, often lead to end-stage liver disease during childhood. We report our experience of DNA-based prenatal diagnosis of PFIC1–3 and Alagille syndrome.

Progressive familial intrahepatic cholestasis (PFIC) and to a lesser extent, Alagille syndrome, often lead to end-stage liver disease during childhood. We report our experience of DNA-based prenatal diagnosis of PFIC1–3 and Alagille syndrome. Four molecular antenatal diagnoses were performed in 3 PFIC families and 17 in 11 Alagille syndrome families. DNA was isolated from chorionic villus or cultured amniocyte samples from women, without pregnancy complications. All four foetuses with a family history of PFIC1, 2, or 3 were heterozygous for an ATP8B1, ABCB11, or ABCB4mutation and pregnancies were continued. Three of the infants were healthy after birth, and 1 premature infant, who had an ABCB4mutation, experienced transient neonatal cholestasis. Among the families with a history of de novo JAG1mutation, none of the foetuses was mutated, versus 40% of those with a history of familial mutation. Of 4 pregnant women with a JAG1-mutated foetus, 3 cut short their pregnancy and 1 gave birth to a child with overt Alagille syndrome. Molecular antenatal diagnosis of PFIC1–3 and Alagille syndrome is reliable because clinical outcome after birth corresponded to molecular foetal data.

Hepatocyte transplantation could be an alternative to whole liver transplantation for the treatment of metabolic liver diseases. However, the results of clinical investigations suggest that the number of engrafted hepatocytes was insufficient to correct metabolic disorders. This may partly result from a lack of proliferation of transplanted hepatocytes. In rodents, portal ligation enhances hepatocyte engraftment after transplantation. We investigated the effects of partial portal ligation and embolization on engraftment and proliferation of transplanted hepatocytes in primates.

Large deletions in WNK1are associated with inherited arterial hypertension. WNK1encodes two types of protein: a kidney-specific isoform (KS-WNK1) lacking kinase activity and a ubiquitously expressed full-length isoform (L-WNK1) with serine threonine kinase activity. Disease is thought to result from hypermorphic mutations increasing the production of one or both isoforms. However, the pattern of L-WNK1 expression remains poorly characterized. We generated transgenic mice bearing a murine WNK1BAC containing the nlacZreporter gene for monitoring L-WNK1 expression during development and adulthood. We observed previously unsuspected early expression in the vessels and primitive heart during embryogenesis, consistent with the early death of WNK1−/−mice. The generalized cardiovascular expression observed in adulthood may also suggest a possible kidney-independent role in blood pressure regulation. The second unsuspected site of L-WNK1 expression was the granular layer and Purkinje cells of the cerebellum, suggesting a role in local ion balance or cell trafficking. In the kidney, discordance between endogenous L-WNK1 and transgene expression suggests that either cis-regulatory elements important for physiological renal expression lie outside the BAC sequence or that illegitimate interactions occur between promoters. Despite this limitation, this transgenic model is a potentially valuable tool for the analysis of spatial and temporal aspects of WNK1 expression and regulation.

Several familial forms of hypertension have been identified, in which the mendelian pattern of inheritance indicated that hypertension results from the alteration of a single gene. This short review focuses on those rare monogenic disorders characterized by a low-renin profile. This common feature reflects that the causative mutations responsible for these disorders all result in an excessive sodium reabsorption in the aldosterone-dependent nephron. Low-renin familial hypertensions with hypokalemia encompass familial hyperaldosteronisms, in which aldosterone levels are elevated, and familial pseudohyperaldosteronisms, mimicking aldosteronism despite appropriately suppressed aldosterone levels. In these disorders, the avidity of the kidney for sodium is because of dysregulated sodium reabsorption through the epithelial sodium channel ENaC and results in potassium wasting and metabolic alcalosis. Familial hypertension with hyperkalemia is a specific syndrome resulting from mutations in at least 3 different genes, among which 2 have been recently identified. These genes encode members of a new family of kinase, the WNK kinases, involved in the regulation of sodium and potassium excretion by the kidney.

L’étude d’une forme rare d’hypertension artérielle de transmission mendélienne, l’hypertension hyperkaliémique familiale (HHF), a récemment permis d’identifier des mutations dans les gènes WNK1et WNK4, qui codent pour des protéines appartenant à une nouvelle famille de sérine-thréonine kinases (with no lysine [K] kinase). Plusieurs éléments du tableau clinique de l’HHF, caractérisé par une hyperkaliémie, une hyperchlorémie et une grande sensibilité aux diurétiques thiazidiques, sont en faveur d’une anomalie du transport ionique dans le tubule distal rénal. En accord avec cette hypothèse, WNK1 et WNK4 sont fortement exprimés dans cette partie du néphron. On les retrouve également dans de nombreux épithéliums impliqués dans le transport du chlore, tels que celui du côlon. In vitro, WNK4 règle à la fois le transport de Na+, K+et Cl−, et pourrait donc constituer une voie de régulation importante des transports ioniques rénal et extra-rénal.

Background & Aims: Most human and animal cholestatic disorders are associated with changes in hepatocyte cytoskeleton and tight junctions (TJs). These changes are usually secondary and nonspecific phenomena, both in intra- and extrahepatic cholestasis. Recently, missense mutations in TJ protein 2 (ZO-2) have been identified in patients with familial hypercholanemia. In the liver, TJs separate bile flow from plasma and are composed of strands of claudins and occludin. We previously assigned a syndrome associating ichthyosis and neonatal sclerosing cholangitis (NISCH syndrome) to chromosome 3q27-q28. We considered claudin-1 to be a strong candidate gene based on its mapping to the minimum interval and on the expression pattern of the mouse ortholog. Methods: The 4 exons and intron-exon junctions of claudin-1 gene were amplified using standard polymerase chain reaction protocols and specific primers. Western blot analysis on cultured fibroblasts and immunohistochemistry on liver tissue section were performed using rabbit anti-claudin-1 antibodies. Results: We described in 4 patients, of 2 inbred kindred of Moroccan origin, a 2-bp deletion (200-201 TT) in exon 1 of the claudin-1 gene arising in a premature stop codon and resulting in total absence of claudin-1 protein in the liver and skin. Conclusions: Lack of claudin-1 in NISCH syndrome may lead to increased paracellular permeability between epithelial cells. Bile duct injury may be related to the absence of claudin-1 expression in cholangiocytes. Our observation, in conjunction with ZO-2-associated hypercholanemia, emphasizes the role played by TJ components in hereditary cholestasis.

Vertebrate myogenesis is controlled by four transcription factors known as the myogenic regulatory factors (MRFs): Myf5, Mrf4, myogenin and MyoD. During mouse development Myf5 is the first MRF to be expressed and it acts by integrating multiple developmental signals to initiate myogenesis. Numerous discrete regulatory elements are involved in the activation and maintenance of Myf5 gene expression in the various muscle precursor populations, reflecting the diversity of the signals that control myogenesis. Here we focus on the enhancer that recapitulates the first phase of Myf5 expression in the epaxial domain of the somite, in order to identify the subset of cells that first transcribes the gene and therefore gain insight into molecular, cellular and anatomical facets of early myogenesis. Deletion of this enhancer from a YAC reporter construct that recapitulates the Myf5 expression pattern demonstrates that this regulatory element is necessary for expression in the early epaxial somite but in no other site of myogenesis. Importantly, Myf5 is subsequently expressed in the epaxial myotome under the control of other elements located far upstream of the gene. Our data suggest that the inductive signals that control Myf5 expression switch rapidly from those that impinge on the early epaxial enhancer to those that impinge on the other enhancers that act later in the epaxial somite, indicating that there are significant changes in either the signalling environment or the responsiveness of the cells along the rostrocaudal axis. We propose that the first phase of Myf5 epaxial expression, driven by the early epaxial enhancer in the dermomyotome, is necessary for early myotome formation, while the subsequent phases are associated with cytodifferentiation within the myotome.