[Analysis of clinical characteristics and variant of NKX2-1 gene in a Chinese boy with Brain-Lung-Thyroid syndrome].

OBJECTIVE: To carry out clinical and genetic analysis for a child featuring Brain-Lung-Thyroid syndrome (BLTS). METHODS: A child who had presented at the Children's Hospital Affiliated to Shandong University on May 27, 2022 was selected as the study subject. Clinical data was collected. Trio-whole exome sequencing (Trio-WES) was carried out for the child and his parents, and candidate variant was verified by Sanger sequencing and bioinformatic analysis. The child was given individualized treatment following the diagnosis. RESULTS: The child, a two-year-and-seven-month-old boy, had presented with global developmental delay, ataxia and hypothyroidism. WES revealed that he has harbored a heterozygous c.674C>T variant of the NKX2-1 gene, based on which he was diagnosed with BLTS. CT scan revealed interstitial and parenchymal inflammation in his lungs, which was reduced by budesonide aerosol inhalation. CONCLUSION: Discovery of the novel c.674C>T variant has enriched the mutational spectrum of the NKX2-1 gene. Budesonide aerosol may be used to treat lung inflammation associated with BLTS.

A Comprehensive Compilation of Data on the Relationship Between Surfactant Protein-B (SFTPB) Polymorphisms and Susceptibility to Neonatal Respiratory Distress Syndrome.

BACKGROUND: This study aims to explore the association between variations in the Surfactant Protein-B (SFTPB) gene and the risk of neonatal respiratory distress syndrome (NRDS). METHODS: A comprehensive literature search was conducted across PubMed, Scopus, EMBASE, and CNKI databases up to February 10, 2024, to identify pertinent studies. RESULTS: A total of seventeen studies examining the +1580 C/T polymorphism (2,058 cases and 2,596 controls) and five studies investigating the -18 A/C polymorphism (680 cases and 739 controls) were included in the analysis. The pooled data indicated that the +1580 C/T polymorphism confers a protective effect against NRDS in various populations and ethnic groups. Conversely, the -18 A/C polymorphism did not demonstrate a significant association either globally or among Asian neonates. CONCLUSIONS: The +1580 C/T variant appears to be protective against NRDS, whereas the -18 A/C polymorphism shows minimal impact on the disease's progression.

The molecular mechanisms that underlie IGHMBP2-related diseases.

Immunoglobulin Mu-binding protein 2 (IGHMBP2) pathogenic variants result in the fatal, neurodegenerative disease spinal muscular atrophy with respiratory distress type 1 (SMARD1) and the milder, Charcot-Marie-Tooth (CMT) type 2S (CMT2S) neuropathy. More than 20 years after the link between IGHMBP2 and SMARD1 was revealed, and 10 years after the discovery of the association between IGHMBP2 and CMT2S, the pathogenic mechanism of these diseases is still not well defined. The discovery that IGHMBP2 functions as an RNA/DNA helicase was an important step, but it did not reveal the pathogenic mechanism. Helicases are enzymes that use ATP hydrolysis to catalyse the separation of nucleic acid strands. They are involved in numerous cellular processes, including DNA repair and transcription; RNA splicing, transport, editing and degradation; ribosome biogenesis; translation; telomere maintenance; and homologous recombination. IGHMBP2 appears to be a multifunctional factor involved in several cellular processes that regulate gene expression. It is difficult to determine which processes, when dysregulated, lead to pathology. Here, we summarise our current knowledge of the clinical presentation of IGHMBP2-related diseases. We also overview the available models, including yeast, mice and cells, which are used to study the function of IGHMBP2 and the pathogenesis of the related diseases. Further, we discuss the structure of the IGHMBP2 protein and its postulated roles in cellular functioning. Finally, we present potential anomalies that may result in the neurodegeneration observed in IGHMBP2-related disease and highlight the most prominent ones.

The Clinical Heterogeneity of Spinal Muscular Atrophy with Respiratory Distress Type 1 (SMARD1)-A Report of Three Cases, Including Twins.

Spinal muscular atrophy with respiratory distress type 1 (SMARD1; OMIM #604320, ORPHA:98920) is a rare autosomal recessive congenital motor neuron disease. It is caused by variants in the IGHMBP2 gene. Clinically, it presents with respiratory failure due to diaphragmatic paralysis, progressive muscle weakness starting in the distal parts of the limbs, dysphagia, and damage to sensory and autonomic nerves. Unlike spinal muscular atrophy (SMA), SMARD1 has a distinct genetic etiology and is not detected in the population newborn screening programs. Most children with SMARD1 do not survive beyond the first year of life due to progressive respiratory failure. Artificial ventilation can prolong survival, but no specific treatment is available. Therapy focuses on mechanical ventilation and improving the patient's quality of life. Research into gene therapy is ongoing. We report three female patients with SMARD1, including twins from a triplet pregnancy. In twin sisters (patient no. 1 and patient no. 2), two heterozygous variants in the IGHMBP2 gene were identified: c.595G>C/p.Ala199Pro and c.1615_1623del/p.Ser539_Tyr541del. In patient no. 3, a variant c.1478C>T/p.Thr493Ile and a variant c.439C>T/p.Arg147* in the IGHMBP2 gene were detected. Our findings underscore the variability of clinical presentations, even among patients sharing the same pathogenic variants in the IGHMBP2 gene, and emphasize the importance of early genetic diagnosis in patients presenting with respiratory failure, with or without associated diaphragmatic muscle paralysis.

Differential diagnosis of Huntington's disease- neurological aspects of NKX2-1-related disorders.

Benign hereditary chorea (BHC) is an inherited neurological disorder consisting of childhood-onset, nonprogressive chorea, generally without any other manifestations. In most reported cases, the inheritance of BHC is autosomal dominant but both incomplete penetrance and variable expressivity are observed and can be caused by NKX2-1 mutations. The spectrum contains choreoathetosis, congenital hypothyroidism, and neonatal respiratory distress syndrome. The neurological symptoms can be misdiagnosed as Huntington's disease (HD). The two Polish families were diagnosed with NKX2-1 gene mutations and a literature review concerning the NKX2-1-related disorders was conducted. All family members were examined by experienced movement disorders specialists. PubMed database was searched to obtain previously described NKX2-1 cases. Whole exome sequencing (WES) was performed in one proband (Family A) and direct NKX2-1 sequencing in the second (Family B). Two Polish families were diagnosed with NKX2-1 gene mutations (p.Trp208Leu and p.Cys117Alafs*8). In one family, the co-occurrence of HD was reported. Forty-nine publications were included in the literature review and symptoms of 195 patients with confirmed NKX2-1 mutation were analyzed. The most common symptoms were chorea and choreiform movements, and delayed motor milestones. The NKX2-1 mutation should always be considered as a potential diagnosis in families with chorea, even with a family history of HD. Lack of chorea does not exclude the NKX2-1-related disorders.

Evaluation of the Copy Number Variants and Single-Nucleotide Polymorphisms of ABCA3 in Newborns with Respiratory Distress Syndrome-A Pilot Study.

Background and Objectives: Respiratory distress syndrome (RDS) in preterm infants commonly occurs due to the immaturity-related deficiency of pulmonary surfactant. Beyond prematurity, various environmental and genetic factors can influence the onset and progression of RDS. This study aimed to analyze three single-nucleotide polymorphisms (SNPs) of the ABCA3 gene to assess the ABCA3 gene as a candidate gene for susceptibility to RDS and overall survival in newborns and to evaluate the utility of MLPA in RDS neonatal patients. Materials and Methods: Three SNPs were chosen and genotyped in a cohort of 304 newborns. Data analysis and statistical tests were employed to examine allele frequencies, haplotypes, and measures of pairwise linkage disequilibrium. Results: There was no observed haplotype association with SNPs rs13332514 (c.1059G>A) and rs170447 (c.1741+33T>C) among newborns, both with and without RDS (p > 0.05). The minor C allele frequency of the ABCA3 rs323043 (c.1755G>C) SNP showed a significant increase in preterm infants with RDS. MLPA results indicated that the predominant findings were normal, revealing no CNVs in the genes ABCA3 and SFTPC that were investigated in our patients. Conclusions: The presence of the variant C allele in the rs323043 (c.1755G>C) SNP may be a risk factor for RDS in premature newborns.

ABCA3 mutation-induced congenital pulmonary surfactant deficiency: A case report.

INTRODUCTION: Congenital surfactant deficiency, often caused by mutations in genes involved in surfactant biosynthesis such as ABCA3, presents a significant challenge in neonatal care due to its severe respiratory manifestations. This study aims to analyze the clinical data of a newborn male diagnosed with pulmonary surfactant metabolism dysfunction type 3 resulting from ABCA3 gene mutations to provide insights into the management of this condition. PATIENT CONCERNS: A newly born male child aged 1 day and 3 hours was referred to our department due to poor crying and shortness of breath. DIAGNOSIS: Primary diagnoses by the duty physicians were: neonatal pneumonia, neonatal respiratory failure, persistent neonatal pulmonary hypertension, birth asphyxia, myocardial damage, and arteriovenous catheterization. Genetic test revealed a compound heterozygous variant in the ABCA3 gene. One allele may be exon variant c.4561C>T, the second allele may be intron variant c.1896 + 2_1896 + 17del. The associated disease included pulmonary surfactant metabolism dysfunction type 3. INTERVENTIONS: He was initially treated with an antiinfective therapeutic regimen. OUTCOMES: The family was informed of this condition and signed off, and the child died. CONCLUSION: Hereditary pulmonary surfactant deficiency is a rare and untreatable disease. The case highlights the challenges in managing congenital surfactant deficiencies and emphasizes the need for heightened awareness of this rare cause of infant respiratory failure.

Descriptive and Functional Genomics in Neonatal Respiratory Distress Syndrome: From Lung Development to Targeted Therapies.

In this up-to-date study, we first aimed to highlight the genetic and non-genetic factors associated with respiratory distress syndrome (RDS) while also focusing on the genomic aspect of this condition. Secondly, we discuss the treatment options and the progressing therapies based on RNAs or gene therapy. To fulfill this, our study commences with lung organogenesis, a highly orchestrated procedure guided by an intricate network of conserved signaling pathways that ultimately oversee the processes of patterning, growth, and differentiation. Then, our review focuses on the molecular mechanisms contributing to both normal and abnormal lung growth and development and underscores the connections between genetic and non-genetic factors linked to neonatal RDS, with a particular emphasis on the genomic aspects of this condition and their implications for treatment choices and the advancing therapeutic approaches centered around RNAs or gene therapy.

Acinar Dysplasia in a Full-Term Newborn with a NKX2.1 Variant.

Acinar dysplasia (AcDys) is one of the three main diffuse developmental disorders of the lung. The transcription factor NK2 homeobox 1 (NKX2.1) partly controls the synthesis of surfactant proteins by type 2 alveolar epithelial cells (AEC2), and germline mutations are known to be associated with brain-lung thyroid syndrome. We report the case of a full-term neonate who developed refractory respiratory failure with pulmonary hypertension requiring venoarterial extracorporeal membrane oxygenation. Histological examination of the lung biopsy specimen was consistent with the diagnosis of AcDys. Molecular analyses led to the identification of the missense heterozygous variant in NKX2.1 (NM_001079668) c.731A>G p.(Tyr244Cys), which is predicted to be pathogenic. After 5 weeks, because AcDys is a fatal disorder and the patient's status worsened, life-sustaining therapies were withdrawn, and she died after a few hours. This study is the first to extend the phenotype of NKX2.1 pathogenic variant, to a fatal form of AcDys.

Integration of multiomics analysis to reveal the major pathways of vitamin A deficiency aggravates acute respiratory distress syndrome in neonatal rats.

Acute respiratory distress syndrome (ARDS) is a major disease that threatens the life and health of neonates. Vitamin A (VA) can participate in early fetal lung development and affect lung immune function. Researches revealed that the serum VA level in premature infants with ARDS was lower than that in premature infants without ARDS of the same gestational age, and premature infants with VA deficiency (VAD) were more likely to develop ARDS. Moreover, the VA levels can be used as a predictor of the development and severity of neonatal ARDS. However, the critical question here is; Does ARDS develop due to VAD in these systemic diseases? Or does ARDS develop because these diseases cause VAD? We hypothesize that VAD may aggravate neonatal ARDS by affecting immunity, metabolism, barriers and other pathways. In this article, we used multiomics analysis to find that VAD may aggravate ARDS mainly through the Fc epsilon RI signaling pathway, the HIF-1 signaling pathway, glutathione metabolism, and valine, leucine and isoleucine degradation signaling pathways, which may provide the molecular pathogenic mechanism behind the pathology of VAD-aggravated ARDS and can also provide potential molecular targets for subsequent research on ARDS.

Cumulative evidence of the genetic association between SP-B C1580T polymorphisms and risk of neonatal respiratory distress syndrome.

Objective: Surfactant protein SP-B, an important protein in pulmonary surfactant, is required for the stabilization of surfactant films in the lung and maintenance of postnatal lung function. Although the association between SP-B polymorphisms and the risk of neonatal respiratory distress syndrome (RDS) has been evaluated, the results have been inconsistent. We investigated the association between SP-B polymorphisms and the risk of neonatal RDS.Methods: Relevant studies were systematically searched in PubMed, EMBASE, Web of Science, and Chinese National Knowledge Infrastructure (CNKI) electronic databases until June 2022. Data were collected independently by two reviewers and converted to odds ratios (ORs) with 95% confidence intervals (CIs). Meta-analysis, subgroup analysis, sensitivity analysis, and publication bias assessment were performed using Stata 12.1 software and Review Manager 5.3.Results: Fourteen studies were included. SP-B C1580T polymorphism was significantly associated with neonatal RDS in five genetic models (T vs. C: OR = 0.70, 95% CI 0.57-0.86, I2 = 78%; TT vs. CC: OR = 0.63, 95% CI 0.53-0.86, I2 = 39%; CT vs. CC: OR = 0.65, 95% CI 0.50-0.84, I2 = 54%; TT + CT vs. CC: OR = 0.62, 95% CI 0.49-0.78, I2 = 59%; TT vs. CC + CT: OR = 0.78, 95% CI 0.67-0.91, I2 = 43%). The CT and TT genotypes may decrease the risk of RDS in neonates. Subgroup analyses revealed that the association of SP-B C1580T polymorphism with neonatal RDS was stable, independent of preterm birth and Hardy-Weinberg equilibrium. In addition, the Han Chinese were more likely to be affected by SP-B C1580T polymorphisms than Caucasians and Finnish.Conclusions: Our findings suggest that SP-B C1580T polymorphism may be a protective factor against neonatal RDS.

Machine learning algorithms and computational validation of single-nucleotide polymorphisms of antioxidant enzymes and oxidative stress markers in neonates.

Aim: To evaluate machine learning algorithms (MLAs) for predicting factors (oxidative stress biomarkers [OSBs] and single-nucleotide polymorphism of the antioxidant enzymes) for respiratory distress syndrome (RDS) and significant alterations in the liver functions (SALVs). Materials & methods: MLAs were applied for predicting the RDS and SALV (with OSB and single-nucleotide polymorphisms in the antioxidant enzymes) with area under the curve (AUC) as the accuracy measure. Results: The C5.0 algorithm best predicted SALV (AUC: 0.63) with catalase as the most important predictor. Bayesian network best predicted RDS (AUC: 0.6) and ENOS1 was the most important predictor. Conclusion: MLAs carry great potential in identifying the potential genetic and OSBs in neonatal RDS and SALV. Validation in prospective studies is needed urgently.

Childbirth usually occurs around 37 weeks of pregnancy. A newborn that is born before this gestational period is referred to as preterm neonate that in many aspects may not have optimum organ functions, in particular, the ability of respiration by lung. This is referred to as respiratory distress syndrome. Respiratory distress syndrome is most often characterized with an imbalance in the molecules that prevent oxidative damage to the cellular molecules (called antioxidants) and those that cause damage (called pro-oxidants). When the balance shifts more to pro-oxidants, it is referred to as oxidative stress. Antioxidant enzymes are key elements for providing appropriate antioxidants in the body. The present study evaluated the role of artificial intelligence (machine learning algorithms in particular) in delineating the role of genetic and oxidative stress biomarkers with oxidative stress in preterm neonates with respiratory distress syndrome. We observed that mutations in certain antioxidant enzymes are associated with respiratory distress syndrome and abnormal liver functions.

First reports of primary ciliary dyskinesia caused by a shared DNAH11 allele in Canadian Inuit.

BACKGROUND: Primary ciliary dyskinesia (PCD) is typically an autosomal recessive disease characterized by recurrent infections of the lower respiratory tract, frequent and severe otitis media, chronic rhinosinusitis, neonatal respiratory distress, and organ laterality defects. While severe lower respiratory tract infections and bronchiectasis are common in Inuit, PCD has not been recognized in this population. METHODS: We report a case series of seven Inuit patients with PCD identified by genetic testing in three Canadian PCD centers. RESULTS: Patients ranged from 4 to 59 years of age (at time of last evaluation) and originated in the Qikiqtaaluk region (Baffin Island, n = 5), Nunavut, or Nunavik (northern Quebec, n = 2), Canada. They had typical features of PCD, including neonatal respiratory distress (five patients), situs inversus totalis (four patients), bronchiectasis (four patients), chronic atelectasis (six patients), and chronic otitis media (six patients). Most had chronic rhinitis. Genetic evaluation demonstrated that all had homozygous pathogenic variants in DNAH11 at NM_001277115.1:c.4095+2C>A. CONCLUSIONS: The discovery of this homozygous DNAH11 variant in widely disparate parts of the Nunangat (Inuit homelands) suggests this is a founder mutation that may be widespread in Inuit. Thus, PCD may be an important cause of chronic lung, sinus, and middle ear disease in this population. Inuit with chronic lung disease, including bronchiectasis or laterality defects, should undergo genetic testing for PCD. Consideration of including PCD genetic analysis in routine newborn screening should be considered in Inuit regions.

The association of angiotensin-converting enzyme gene polymorphism with respiratory distress syndrome in premature neonates.

BACKGROUND: There was a contradiction in the previous literature on whether the D/D genotype of angiotensinconverting enzyme (ACE) is a protective or risk factor for respiratory distress syndrome (RDS) in premature neonates. To solve this debate, we intended to examine the association between ACE gene polymorphism and RDS in premature neonates. METHODS: We enrolled a total of 100 premature neonates with gestational age below 37 weeks. They were divided into 2 groups, the case group included 50 premature neonates diagnosed with RDS. While the control group included 50 premature neonates with no signs of RDS. We assessed ACE gene polymorphism using polymerase chain reaction. All neonates underwent chest x-ray, echocardiography, and routine laboratory investigations. RESULTS: D/D and D/I genotypes were higher in the control group (48% and 50%) than in the case group (26% and 40%). Whereas, I/I genotype was lower in the control group (2%) than in the case group (34%) (p < 0.001). By counting D alleles among members of both groups, D-alleles were significantly higher in the control group (73%) than in the case group (46%) (p < 0.001). CONCLUSIONS: In premature neonates, D/D and D/I genotypes and D-alleles are protective factors for RDS. Whereas, I/I genotype and I-alleles are associated with the incidence of RDS with complications.

Association of umbilical cord blood miR-375 with neonatal respiratory distress syndrome and adverse neonatal outcomes in premature infants.

BACKGROUND: Neonatal respiratory distress syndrome (NRDS) is a common respiratory disorder occurring in premature infants, and some microRNAs (miRNAs) have been demonstrated to play critical roles in NRDS progression. This study aimed to measure relative expression of miR-375 in infants with NRDS, and further evaluate the clinical significance of miR-375 in predicting the onset and clinical prognosis of NRDS in infants. METHODS: This study collected umbilical cord blood from 180 premature neonates, including 90 neonates with NRDS and 90 non-NRDS neonates. Quantitative real-time PCR was used to detect relative expression level of miR-375. The diagnostic value of miR-375 in screening NRDS neonates from control neonates and its predictive accuracy for clinical prognosis were evaluated by receiver operating characteristic analysis. The relationship of miR-475 with disease onset and clinical outcomes in NRDS infants was assessed by univariate and multivariate logistic regression analyses. RESULTS: Relative miR-375 expression was upregulated in NRDS neonates, and high levels of miR-375 were observed in NRDS grade III-IV cases compared to those early-stage neonates. miR-375 had relatively high diagnostic accuracy to screen NRDS neonates and was independently associated with NRDS onset in infants. Moreover, relative miR-375 expression was upregulated in NRDS neonates with poor prognosis and could independently predict the clinical outcomes of NRDS neonates with considerable predictive accuracy. CONCLUSION: Umbilical cord serum miR-375 is elevated and associated with NRDS onset and clinical outcomes in NRDS neonates. Thus, miR-375 may serve as a biomarker for the diagnosis and prognosis of infants with NRDS.

Spinal muscular atrophy with respiratory distress type 1 (SMARD1): a rare cause of hypotonia, diaphragmatic weakness, and respiratory failure in infants.

BACKGROUND: Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a very rare autosomal recessive disorder caused by mutations in the immunoglobulin µ-binding protein-2 (IGHMBP2) gene on chromosome 11q13.2-q13.4. The initial symptoms of patients with SMARD1 are respiratory distress and distal muscle weakness manifesting in the infantile period due to progressive degeneration of α-motor neurons. Preterm birth, intrauterine growth retardation, feet deformities, sensory and autonomic neuropathy are other main features. CASE: Herein, we report the characteristics of a 6-year-old Turkish girl with a diagnosis of SMARD1 confirmed by homozygous c.1738G > A (p.Val580Ile) missense IGHMBP2 variant. She had unusual features such as vocal cord paralysis, nystagmus, and lack of congenital foot deformities besides typical findings including hypotonia, respiratory distress, and diaphragmatic weakness in the early infantile period. Epileptic seizures, cognitive impairment, and brain magnetic resonance imaging (MRI) abnormalities were other, unexpected, features which developed during the course of the disorder possibly due to several hypoxic episodes. CONCLUSIONS: SMARD1 should be kept in mind in hypotonic infants with diaphragmatic weakness and respiratory failure during the early infantile period, even in the presence of unexpected findings including vocal cord paralysis, nystagmus, epileptic seizures, and brain MRI abnormalities.

High-Content Screening Identifies Cyclosporin A as a Novel ABCA3-Specific Molecular Corrector.

ABCA3 (ATP-binding cassette subfamily A member 3) is a lipid transporter expressed in alveolar type II cells and localized in the limiting membrane of lamellar bodies. It is crucial for pulmonary surfactant storage and homeostasis. Mutations in the ABCA3 gene are the most common genetic cause of respiratory distress syndrome in mature newborns and of interstitial lung disease in children. Apart from lung transplant, there is no cure available. To address the lack of causal therapeutic options for ABCA3 deficiency, a rapid and reliable approach is needed to investigate variant-specific molecular mechanisms and to identify pharmacologic modulators for monotherapies or combination therapies. To this end, we developed a phenotypic cell-based assay to autonomously identify ABCA3 wild-type-like or mutant-like cells by using machine learning algorithms aimed at identifying morphologic differences in wild-type and mutant cells. The assay was subsequently used to identify new drug candidates for ABCA3-specific molecular correction by using high-content screening of 1,280 Food and Drug Administration-approved small molecules. Cyclosporin A was identified as a potent corrector, specific for some but not all ABCA3 variants. Results were validated by using our previously established functional small-format assays. Hence, cyclosporin A may be selected for orphan drug evaluation in controlled repurposing trials in patients.

Lipocalin-2 silencing suppresses inflammation and oxidative stress of acute respiratory distress syndrome by ferroptosis via inhibition of MAPK/ERK pathway in neonatal mice.

Neonatal acute respiratory distress syndrome (ARDS) has high morbidity and mortality rates worldwide, but there is a lack of pharmacologic treatment and clinical targeted therapies. In this study, we aimed to explore the effects of Lipocalin-2 (LCN2) on ferroptosis-mediated inflammation and oxidative stress in neonatal ARDS and the potential mechanism. In this study, we established an in vivo ARDS mouse model and an in vitro ARDS cell model by LPS (Lipopolysaccharide) stimulation. Lung tissue injury was evaluated by wet/dry ratios and histopathological examination. LCN2 expression was detected by qRT-PCR and Western blot. Inflammatory factors, oxidative stress and apoptosis were also detected. Ferroptosis was identified by detection of Fe2+ level and ferroptosis-associated protein expressions. Mitogen-activated protein kinases (MAPK)/extracellular signal-regulated kinase (ERK) pathway signaling was examined by Western blot analysis. The data revealed that LCN2 expression was significantly upregulated in neonatal mice with ARDS. Interference with LCN2 protected LPS-induced lung in neonatal mouse by reducing the radio of wet/dry and alleviating pathological damages. In addition, LCN2 silencing repressed LPS-induced inflammation, oxidative stress in vivo and in vitro, as well as apoptosis. Meanwhile, decreased level of Fe2+ and transferrin while increased levels of ferritin heavy chain 1 (FTH1) and glutathione peroxidase 4 (GPX4) were observed. The expression MAPK/ERK pathway was inhibited by depletion of LCN2. The present results suggest that LCN2 knockdown protected LPS-induced ARDS model via inhibition of ferroptosis-related inflammation and oxidative stress by inhibiting the MAPK/ERK pathway, thereby presenting a novel target for the treatment of ARDS.

Role of surfactant protein C in neonatal genetic disorders of the surfactant system: A case report.

RATIONALE: Respiratory distress syndrome (RDS) refers to the symptoms of progressive dyspnea and respiratory failure in newborns shortly after birth. The clinical and genetic characteristics of patients with neonatal RDS have not been extensively reported. PATIENT CONCERNS: A infant was in critical condition with repeated paroxysmal blood oxygen decline. Oxygen inhalation and noninvasive ventilator-assisted breathing relief were not effective. The etiology was unclear, and there was no family history of lung disease. Surface-active substance replacement therapy and positive pressure-assisted ventilation support were ineffective. DIAGNOSIS: The infant was clinically diagnosed with RDS. Genetic tests revealed a heterozygous missense mutation in the c.168 surfactant protein C (SFTPC) gene. INTERVENTIONS: Tracheal intubation was performed with invasive ventilator-assisted breathing, pulmonary surfactant was administered. Supportive treatment for liver protection and administration of a cardiotonic diuretic, vasodilator, human immunoglobulin (intravenous infusion), fresh frozen plasma, and suspended red blood cells were performed. OUTCOMES: The infant showed poor responses to respiratory and circulatory support, antibiotic treatment, and other treatment methods. The patient was discharged from hospital against the advice of us, cut off from us. The long-term prognosis of the patient after discharge remains unknown. LESSONS: SFTPC gene mutations may be an important risk factor for the development of common lung diseases. Because of the important roles of surfactant functions and metabolism, mutations in these genes can affect the production and function of pulmonary surfactant, leading to severe lung disease in term newborns.

Models for IGHMBP2-associated diseases: an overview and a roadmap for the future.

Models are practical tools with which to establish the basic aspects of a diseases. They allow systematic research into the significance of mutations, of cellular and molecular pathomechanisms, of therapeutic options and of functions of diseases associated proteins. Thus, disease models are an integral part of the study of enigmatic proteins such as immunoglobulin mu-binding protein 2 (IGHMBP2). IGHMBP2 has been well defined as a helicase, however there is little known about its role in cellular processes. Notably, it is unclear why changes in such an abundant protein lead to specific neuronal disorders including spinal muscular atrophy with respiratory distress type 1 (SMARD1) and Charcot-Marie-Tooth type 2S (CMT2S). SMARD1 is caused by a loss of motor neurons in the spinal cord that results in muscle atrophy and is accompanied by rapid respiratory failure. In contrast, CMT2S manifests as a severe neuropathy, but typically without critical breathing problems. Here, we present the clinical manifestation of IGHMBP2 mutations, function of protein and models that may be used for the study of IGHMBP2-associated disorders. We highlight the strengths and weaknesses of specific models and discuss the orthologs of IGHMBP2 that are found in different systems with regard to their similarity to human IGHMBP2.