No abstract available.
Adult ; Amino Acid Sequence ; Bone Marrow/metabolism/pathology ; Chromosomes, Human, Pair 21 ; Chromosomes, Human, Pair 8 ; Core Binding Factor Alpha 2 Subunit/*genetics ; Exons ; Female ; Humans ; INDEL Mutation ; Leukemia, Myeloid, Acute/*genetics/pathology ; Multiplex Polymerase Chain Reaction ; Proto-Oncogene Proteins/*genetics ; Proto-Oncogene Proteins c-kit/*genetics ; Transcription Factors/*genetics ; *Translocation, Genetic

Most cases of microcephaly with growth failure and developmental delay have a genetic or metabolic etiology. Whole-exome sequencing (WES) has uncovered many causative genes and has also broadened their phenotypic spectrum. The present study applied WES to a boy with microcephaly, growth failure, developmental delay, seizures and atopic dermatitis, which reveal an unexpected frame-shift mutation (c.1248_1253delinsCT, NM_014009.3; p.Lys416Asnfs, NP_054728.2) in the forkhead box P3 gene (FOXP3). Mutations of this gene are known to result in immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Mutation of FOXP3 was reverified by Sanger sequencing in the proband and his carrier mother. Flow-cytometry expression study of FOXP3 in peripheral white blood cells showed that the mean fluorescence intensity of FOXP3 was lower in the proband than in a normal control. We report a mild form of IPEX syndrome without chronic protracted diarrhea or major infections, instead presenting with proportional microcephaly, growth failure, developmental delay, seizures and atopic dermatitis.
Dermatitis, Atopic ; Diarrhea ; Failure to Thrive ; Fluorescence ; Growth and Development ; Humans ; Leukocytes ; Male ; Microcephaly* ; Mothers ; Seizures

Progressive cerebellar ataxias are rare diseases during childhood, especially under 6 years of age. In a single family, three affected siblings exhibited Friedreich's-ataxia-like phenotypes before 2 years of age. They had progressive cerebellar atrophy, intellectual disability, and scoliosis. Although their phenotypes were similar to those observed in patients with autosomal recessive cerebellar ataxias, other phenotypes (e.g., seizure, movement disorders, ophthalmologic disturbance, cardiomyopathy, and cutaneous disorders) were not noted in this family. Whole-exome sequencing of the family members revealed one potential heterozygous mutation (c.1209delG, NM_181733.2; p.Met403IlefsX3, NP_859422.2) of the gene encoding conserved oligomeric Golgi complex subunit 5 (COG5). The heterozygous deletion at the fifth base in exon 12 of COG5 caused a frameshift and premature stop. Western blotting of COG5 proteins in the skin tissues from an affected proband showed a significantly decreased level of full length COG5 and smaller, aberrant COG5 proteins. We reported a milder form of COG5 defect showing Friedreich's-ataxia-like phenotypes without hypotonia, microcephaly, and short stature that were observed in most patients with COG5 defect.
Atrophy* ; Blotting, Western ; Cardiomyopathies ; Cerebellar Ataxia ; Child ; Exons ; Golgi Apparatus ; Humans ; Intellectual Disability ; Microcephaly ; Movement Disorders ; Muscle Hypotonia ; Phenotype* ; Rare Diseases ; Scoliosis ; Seizures ; Siblings ; Skin

Background: Observational studies of the ongoing coronavirus disease 2019 (COVID-19) outbreak suggest that a ‘cytokine storm’ is involved in the pathogenesis of severe illness.However, the molecular mechanisms underlying the altered pathological inflammation in COVID-19 are largely unknown. We report here that toll-like receptor (TLR) 4-mediated inflammatory signaling molecules are upregulated in peripheral blood mononuclear cells (PBMCs) from COVID-19 patients, compared with healthy controls (HC). Methods: A total of 48 subjects including 28 COVID-19 patients (8 severe/critical vs. 20 mild/ moderate cases) admitted to Chungnam National University Hospital, and age/sex-matched 20 HC were enrolled in this study. PBMCs from the subjects were processed for nCounter Human Immunology gene expression assay to analyze the immune related transcriptome profiles. Recombinant proteins of severe acute respiratory syndrome coronavirus-2 (SARSCoV-2) were used to stimulate the PBMCs and monocyte-derived macrophages, and real-time polymerase chain reaction was performed to quantify the mRNA expressions of the proinflammatory cytokines/chemokines. Results: Among the most highly increased inflammatory mediators in severe/critically ill patients, S100A9, an alarmin and TLR4 ligand, was found as a noteworthy biomarker, because it inversely correlated with the serum albumin levels. We also observed that recombinant S2 and nucleocapsid proteins of SARS-CoV2 significantly increased proinflammatory cytokines/chemokines and S100A9 in human primary PBMCs. Conclusion These data support a link between TLR4 signaling and pathological inflammation during COVID-19 and contribute to develop therapeutic approaches through targeting TLR4-mediated inflammation.