Genetic analysis of a Fanconi anemia case revealed the presence of FANCF mutation (exon 1;469>C-T) with implications to develop acute myeloid leukemia.

BACKGROUND: Fanconi anemia (FA) is a rare genetic disorder and one of the most common inherited forms of aplastic anemia. FA is an autosomal recessive or X-linked genetic disorder that is characterized by typical physical malformations and haematopoietic anomalies. In most cases of FA, patients harbor homozygous or double heterozygous mutations in the FANCA (60-65%), FANCC (10-15%), FANCG (~ 10%), FANCD2 (3-6%) or FANCF (2%) genes in different ethnic populations, which leads to inherited bone marrow failure (IBMF). Hence, it is important to screen such mutations in correlation with clinical manifestations of FA in various ethnic populations. APPROACH: An 11 year old female pediatric patient of an East India family was presented with febrile illness, having thrombocytopenia with positive dengue IgM (Immunoglobulin M) and treated as a case of dengue hemorrhagic fever at the initial stage of diagnosis. Chromosomal breakage study was performed based on the abnormal physical examination, which showed 100% breaks, triradials, and quadrilaterals in mitomycin (MMC)-induced peripheral blood lymphocyte culture. Importantly, conventional cytogenetic assay in most of the bone marrow cells revealed an additional gain in chromosome 3q+ [46,XX,add(3)(q25)] and terminal loss in chr8p- [46,XX,del(8)(p23)], which might have a prognostic relevance in the outcomes of the FA patient. The bone marrow aspiration and biopsy were repeated and the results showed acute leukemia with 39% blast cells. Whole-genome sequencing analysis of the patient confirmed the presence of (exon 1; 496 > C-T) non-sense mutation leading to a truncated FANCF protein attributed to a stop codon at the amino acid position 166. CONCLUSION: The study reported the presence of a homozygous C-T exon 1 mutation in FANCF gene in the female pediatric patient from Odisha, India associated with FA. Furthermore, both parents were found to be carriers of FANCF gene mutation, as this allele was found to be in heterozygous state upon genome sequencing. The pathogenicity of the agent was robustly supported by the clinical phenotype and biochemical observations, wherein the patient eventually developed acute myeloid leukemia. The findings of the study infer the importance of early detection of FA and the associated mutations, which might lead to the development of acute myeloid leukemia.

Role of endoplasmic reticulum stress-related unfolded protein response and its implications in dengue virus infection for biomarker development.

Dengue virus (DENV) causes debilitating disease in humans, which varies at different rates in host cells, such as monocytes, macrophages, dendritic cells, Langerhans cells, and other cell types. Such heterogeneity in DENV infection in cells could be attributed to a range of factors, including host cell immune response, anti-viral cellular proteins, and virus mediated cellular autophagy. This review delineates an important feature of every cell, the unfolded protein response (UPR) that is attributed to the accumulation of several viral and unfolded/misfolded proteins, such as in DENV infection. UPR is a normal process to counteract endoplasmic reticulum (ER) stress that leads to cell autophagy; though the phenomenon is markedly upregulated during DENV infection. This could be attributed to the uncontrolled activation of the key UPR signaling pathways: inositol-requiring transmembrane kinase/endoribonuclease 1 (IRE1), protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), and activating transcription factor-6 (ATF6), which promote cell autophagy under normal and diseased conditions through the downstream regulation of apoptosis promoting factors such as X-box binding protein (XBP1), GADD34, and ATF-6. Because DENV can modulate these signaling cascades, by promoting dysregulated cell autophagy, the ER stress mediated UPR pathways and the inherent agents could play an important role in delineating the severity of dengue infection with a potential for developing DENV targeted therapeutics.