Molecular Analysis of The First Reported Hereditary Lymphedema-Distichiasis Case in Bangladesh

BackgroundLymphedema–distichiasis syndrome (LD, OMIM 153400) is a hereditary primary lymphedema with autosomal dominant nature of inheritance and variable expression. LD is characterized by late childhood or pubertal onset of lower limb lymphedema and an aberrant second row of eyelashes (distichiasis) arising from the meibomian glands. Underlying molecular causes include mutations in the FOXC2 gene, which codes for a forkhead transcription factor involved in the development of the lymphatic and vascular system. ResultsIn this study, we report the first case of LD from Bangladesh with classical lymphedema–distichiasis syndrome who carries an eight-base-pair deletion in the FOXC2 -gene. ClinVar accession code for this deletion is RCV000007679.3. Although most other mutations of this gene are unique among different families, literature survey indicates this 8 bp deletion has been reported multiples times in independent studies for families from different geographical regions. ConclusionFOXC2 protein is 501 amino acid long. This deletion of 8 bp (ACGCCGCC) causes frameshift of codons after amino acid number 304. The frameshift creates an altered truncated protein with 154 newly amino acids after codon 304. We assume that these changes in the protein may affect its function contributing to the disease manifestations. Further research may confirm these assumptions.

Forkhead transcription factor FKH-8 is a master regulator of primary cilia in C. elegans

SUMMARYCilia, either motile or non-motile (a.k.a primary or sensory), are complex evolutionary conserved eukaryotic structures composed of hundreds of proteins required for their assembly, structure and function that are collectively known as the ciliome. Ciliome mutations underlie a group of pleiotropic genetic diseases known as ciliopathies. Proper cilium function requires the tight coregulation of ciliome gene transcription, which is only fragmentarily understood. RFX transcription factors (TF) have an evolutionarily conserved role in the direct activation of ciliome genes both in motile and non-motile cilia cell types. In vertebrates, FoxJ1 and FoxN4 Forkhead (FKH) TFs work with RFX in the direct activation of ciliome genes, exclusively in motile cilia cell-types. No additional TFs have been described to act together with RFX in primary cilia cell-types in any organism. Here we describe FKH-8, a FKH TF, as master regulator of the primary ciliome in Caenorhabditis elegans. fkh-8 is expressed in all ciliated neurons in C. elegans, binds the regulatory regions of ciliome genes, regulates ciliome gene expression, cilium morphology and a wide range of behaviours mediated by sensory cilia. Importantly, we find FKH-8 function can be replaced by mouse FOXJ1 and FOXN4 but not by members of other mouse FKH subfamilies. In conclusion, our results show that RFX and FKH TF families act as master regulators of ciliogenesis also in sensory ciliated cell types and suggest that this regulatory logic could be an ancient trait predating functional cilia sub-specialization.

Lineage-specific control of convergent differentiation by a Forkhead repressor

During convergent differentiation, multiple developmental lineages produce a highly similar or identical cell type. However, few molecular players that drive convergent differentiation are known. Here, we show that the C. elegans Forkhead transcription factor UNC-130 is required in only one of three convergent lineages that produce the same glial cell type. UNC-130 acts transiently as a repressor in progenitors and newly-born terminal cells to allow the proper specification of cells related by lineage rather than by cell type or function. Specification defects correlate with UNC-130:DNA binding, and UNC-130 can be functionally replaced by its human homolog, the neural crest lineage determinant FoxD3. We propose that, in contrast to terminal selectors that activate cell-type specific transcriptional programs in terminally differentiating cells, UNC-130 acts early and specifically in one convergent lineage to produce a cell type that also arises from molecularly distinct progenitors in other lineages.

Role of FOXO1 in Glucocorticoid-Induced Somatotrope Maturation

Growth hormone (GH) is a well-known metabolic factor secreted by pituitary somatotropes. Transcription factors such as POU1F1 and NEUROD4 promote somatotrope differentiation, maturation, and function. The forkhead transcription factor, FOXO1, is necessary for the proper timing of somatotrope differentiation and function, but the underlying mechanisms behind it have yet to be unraveled. Pituitary gland development also depends on regulation by signaling factors and hormones. Glucocorticoids have mixed effects on growth hormone production. However, when the effects of glucocorticoid signaling on the hypothalamus and pituitary gland are uncoupled, the direct effects of glucocorticoid signaling on pituitary somatotropes are not only stimulatory, but necessary for initiation of somatotrope maturation and for maintenance of somatotrope function. We find that FOXO1 is necessary for glucocorticoid induction of important somatotrope genes. Activation of glucocorticoid signaling in the somatotrope-derived MtT/S cell line induces transient expression of the bZIP transcription factor, Crebl2 within 2 hours. Interestingly, glucocorticoid induction of Crebl2 as well as the somatotrope genes Ghrhr and Gh1, is impaired in the presence of the FOXO1 inhibitor (AS1842856). There are several possible mechanisms underlying the requirement of FOXO1 in glucocorticoid induction of somatotrope maturation. One possible mechanism is that glucocorticoid signaling upregulates expression of Foxo1 and ultimately FOXO1 targets. Consistent with this possibility, Foxo1 expression is induced 8 hours after activation of glucocorticoid signaling. This does not appear to be the only mechanism underlying the role for FOXO1 in mediating glucocorticoid-induced somatotrope maturation, however, because many FOXO1 target genes, such as Neurod4 and Fosl2 are not affected by glucocorticoid signaling. We are currently investigating whether cooperative binding between FOXO1 and the glucocorticoid receptor contributes to transcriptional regulation of common targets genes. Together these data demonstrate that FOXO1 is a key factor mediating glucocorticoid induction of somatotrope maturation.

The Levels of FoxO3a Predict the Failure of Imatinib Mesylate Therapy among Chronic Myeloid Leukemia Patients

INTRODUCTION: Forkhead Transcription Factor 3a (FoxO3a) has been proposed to have a high efficacy to predict the failure of imatinib mesylate (IM) therapy among Chronic Myeloid Leukemia (CML) patients. However, the limited evidence had made this marker remained controversy. OBJECTIVES: We aimed to investigate the correlation between the levels of FoxO3a and the risk of treatment failure of IM therapy in CML patients. METHODS: A prospective cohort study was carried out between February 2019 and February 2020 in Saiful Anwar Hospital, Malang, Indonesia. All CML patients treated with IM on our hospital during the study period were included. The levels of FoxO3a was determined using the Enzyme-linked immunosorbent assay (ELISA) using Cusabio Biotech Kit (Cusabio Biotech Co., New York, USA). The treatment response was assessed using the European Leukemia criteria. The correlation and effect estimate between the levels of FoxO3a and treatment response of CML patients was assessed using multiple logistic regression. RESULTS: 53 CML patients receiving IM in our hospital were included, consisting of 29 patients with good response and 24 patients with non-response. Our study found that CML patients with lower levels of FoxO3a was associated with increased risk to develop treatment failure when treated with IM. Moreover, we also found that higher risk of treatment failure of IM therapy was also found in patients with increased levels of thrombocytes, basophils, and leukocytes, and lower levels of hemoglobin. CONCLUSION: We reveal that FoxO3a is the prominent marker to predict the treatment response of CML patients treated with IM.

Involvement of Transcription Factor FoxO1 in the Pathogenesis of Polycystic Ovary Syndrome

FoxO1 is a member of the forkhead transcription factor family subgroup O (FoxO), which is expressed in many cell types, and participates in various pathophysiological processes, including cell proliferation, apoptosis, autophagy, metabolism, inflammatory response, cytokine expression, immune differentiation, and oxidative stress resistance. Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in the women of childbearing age, which is regulated via a variety of signaling pathways. Currently, the specific mechanism underlying the pathogenesis of PCOS is still unclear. As an important transcription factor, FoxO1 activity might be involved in the pathophysiology of PCOS. PCOS has been associated with insulin resistance and low-grade inflammatory response. Therefore, the studies regarding the role of FoxO1 in the incidence and associated complications of PCOS will help provide novel ideas for establishing the treatment strategy of PCOS.

Vitiligo and chronic autoimmune thyroiditis

Vitiligo, the discoloration of the skin, has different autoimmune mechanisms reflected by many biomarkers as shown by skin histology, staining for CD4 and CD8 T lymphocytes, chemokine ligand 9 or circulating cytokines such as interleukin (IL)-1 beta, interferon (IFN)-gamma, transforming growth factor (TGF)-beta, antibodies, markers of oxidative stress, chemokines, and others. In this narrative review, we aim to overview vitiligo in relationship with chronic autoimmune thyroiditis. Regarding vitiligo, more than 50 different genetic loci have been associated with this disease, and the heritability is high. There is a 20% risk of an environmental connection which may also act as a trigger; moreover, the association with human leukocyte antigen (HLA) expression is well recognized. The specific lesions display CD8+ tissue-resident memory T cells as continuous key activators of melanocytes. The association with chronic thyroiditis is based on common autoimmune background and excessive reactive oxygen species that destroy melanocytes and thyrocytes (oxidative stress hypothesis) with thyroxine and melanin as target molecules, thus sharing a common origin: tyrosine. Moreover, common epigenetic anomalies or mutations of the Forkhead transcription factor D3 (FOXD3) have been described. Since vitiligo affects up to 1–2% of the population worldwide and 34% of patients have positive thyroid antibodies, apart from common autoimmunity background and oxidative stress toxicity, the association is clinically relevant for different practitioners.