Generalized Lymphatic Dysplasia (GLD) is a rare form of primary lymphedema characterized by a uniform, widespread lymphedema affecting all segments of the body, with systemic involvement such as intestinal and/or pulmonary lymphangiectasia, pleural effusions, chylothoraces and/or pericardial effusions. This may present prenatally as non-immune hydrops. Here we report homozygous and compound heterozygous mutations in PIEZO1 resulting in an autosomal recessive form of GLD with a high incidence of non-immune hydrops fetalis (NIHF) and childhood onset of facial and four limb lymphedema. Mutations in PIEZO1, which encodes a mechanically activated ion channel, have been reported with autosomal dominant Dehydrated Hereditary Stomatocytosis (DHS) and non-immune hydrops of unknown etiology. Besides its role in red blood cells, our findings indicate that PIEZO1 is also involved in the development of lymphatic structures.

Hydrops fetalis describes fluid accumulation in at least 2 fetal compartments, including abdominal cavities, pleura, and pericardium, or in body tissue. The majority of hydrops fetalis cases are nonimmune conditions that present with generalized edema of the fetus, and approximately 15% of these nonimmune cases result from a lymphatic abnormality. Here, we have identified an autosomal dominant, inherited form of lymphatic-related (nonimmune) hydrops fetalis (LRHF). Independent exome sequencing projects on 2 families with a history of in utero and neonatal deaths associated with nonimmune hydrops fetalis uncovered 2 heterozygous missense variants in the gene encoding Eph receptor B4 (EPHB4). Biochemical analysis determined that the mutant EPHB4 proteins are devoid of tyrosine kinase activity, indicating that loss of EPHB4 signaling contributes to LRHF pathogenesis. Further, inactivation of Ephb4 in lymphatic endothelial cells of developing mouse embryos led to defective lymphovenous valve formation and consequent subcutaneous edema. Together, these findings identify EPHB4 as a critical regulator of early lymphatic vascular development and demonstrate that mutations in the gene can cause an autosomal dominant form of LRHF that is associated with a high mortality rate.

Molecular systematic analysis of the annexin gene superfamily characterized the evolutionary origin, frequency and range of structural variation in calcium interaction domains that are considered intrinsic for membrane targeting and ion channel function. Approximately 36% of annexin repeat domains in an estimated 100 distinct subfamilies contained amino acid changes consistent with the functional loss of type two calcium-binding sites. At least 11% of annexin domains contained a novel K/H/RGD motif conserved in particular subfamilies and manifest in all phyla, apparently via convergent evolution. The first yeast annexin from Yarrowia lipolytica was classified in the ANXC1 subfamily with fungal and mycetozoan representatives. This clade had intact calcium-binding sites but disruption of the normally well-conserved, mid-repeat 4 region implicated in calcium channel regulation. Conversely, a tandem pair of novel annexins from the amphioxus Branchiostoma floridae resembled annexin A13 in gene structure and conserved the charged amino acids associated with the internal hydrophilic pore, but were devoid of external type 2 calcium-binding sites and incorporated K/RGD motifs instead, like annexin A9. The selective erosion of calcium-binding sites in annexin domains and the occurrence of alternate ligands in the same exposed, interhelical loops are pervasive features of the superfamily. This suggests greater complexity than previously appreciated in the mechanisms controlling annexin membrane interaction and calcium channel operation.

PIEZO1 is a large mechanosensitive ion channel protein. Diseases associated with PIEZO1 include autosomal recessive generalised lymphatic dysplasia of Fotiou (GLDF) and autosomal dominant dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal oedema (DHS). The two disorders show overlapping features, fetal hydrops/perinatal oedema have been reported in both. Electrophysiological studies suggest opposite mechanisms of action: the mutations identified in GLDF patients cause a loss-of-function mechanism of disease and mutations in DHS patients cause gain of function. This raises the question: Is the pathogenic disease mechanism behind the fetal oedema the same in the two phenotypes? In this Symposium Review, we will discuss the two conditions and highlight key questions that remain to be answered. For instance, the perinatal oedema often resolves soon after birth and we are still at a loss to understand why. Are there any mechanisms which could compensate for the faulty PIEZO1 in these patients? Are there physiological changes at birth that are less reliant on the function of PIEZO1? Thus, there is a clear need for further studies into the two disorders, in order to fully understand the role of PIEZO1 in health and disease.

Background: In quiescent endothelial cells, the transcription factor Erg regulates cell homeostasis by repressing expression of proinflammatory genes.Results: Erg represses NF-κB p65-dependent transcription of ICAM-1, partly by inhibiting p65 binding to DNA.Conclusion: Erg acts as a gatekeeper in quiescent endothelial cells to inhibit basal NF-κB activity.Significance: Novel pathway controlling endothelial cell activation and inflammation.

Primary lymphedema is a long-term (chronic) condition characterized by tissue lymph retention and swelling that can affect any part of the body, although it usually develops in the arms or legs. Due to the relevant contribution of the lymphatic system to human physiology, while this review mainly focusses on the clinical and physiological aspects related to the regulation of fluid homeostasis and edema, clinicians need to know that the impact of lymphatic dysfunction with a genetic origin can be wide ranging. Lymphatic gene dysfunction can affect immune function so leading to infection; it can influence cancer development and spread; and it can determine fat transport so impacting on nutrition and obesity. Genetic studies and the development of imaging techniques for the assessment of lymphatic function have enabled the recognition of primary lymphedema as a heterogenic condition in terms of genetic causes and disease mechanisms. In this review, the known biological function of several genes crucial to the development and function of the lymphatic system are used as a basis for understanding normal lymphatic biology. The disease conditions originating from mutations in these genes are discussed together with a detailed clinical description of the phenotype and the up-to-date knowledge in terms of disease mechanisms acquired from in vitro and in vivo research models.

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