Congenital pulmonary alveolar proteinosis in a neonate / 中国当代儿科杂志

The male patient was referred to the hospital at 44 days old due to dyspnea after birth and inability to wean off oxygen. His brother died three days after birth due to respiratory failure. The main symptoms observed were respiratory failure, dyspnea, and hypoxemia. A chest CT scan revealed characteristic reduced opacity in both lungs with a "crazy-paving" appearance. The bronchoalveolar lavage fluid (BALF) showed periodic acid-Schiff positive proteinaceous deposits. Genetic testing indicated a compound heterozygous mutation in the ABCA3 gene. The diagnosis for the infant was congenital pulmonary alveolar proteinosis (PAP). Congenital PAP is a significant cause of challenging-to-treat respiratory failure in full-term infants. Therefore, congenital PAP should be considered in infants experiencing persistently difficult-to-treat dyspnea shortly after birth. Early utilization of chest CT scans, BALF pathological examination, and genetic testing may aid in early diagnosis.

Advance in ABCA3 gene mutation and related pediatric pulmonary diseases / 国际儿科学杂志

ATP-binding cassette transporter A3(ABCA3) gene mutation is one of the important causes of severe respiratory distress syndrome and interstitial lung disease in children and adults.Clinical phenotypes vary dramatically among patients with ABCA3 mutations.So far, the genotype-phenotype correlation is not entirely clear.The association between the possible factors that influence the phenotypes, such as the environment, infection and diseases remains to be studied.There is no specific treatment for the diseases caused by the mutations.Present models for studying ABCA3 mutations in vitro are still to be improved.This article focuses on reviewing the structure, genetics and the research progress of treatment of ABCA3 gene mutation related pediatric diseases, in order to provide experience and ideas for further researches and treatment of the diseases caused by ABCA3 gene mutation.

Disfunción del transportador del surfactante pulmonar ABCA3: reporte de un caso peruano / Surfactant ABCA3 transporter dysfunction: a case report from Peru

Resumen Introducción: Los trastornos genéticos que afectan la homeostasis del surfactante pulmonar son una causa importante del síndrome de dificultad respiratoria en el recién nacido a término y de enfermedad pulmonar intersticial difusa en niños. El transportador ABCA3 (ATP binding cassette A3) interviene en la producción normal del surfactante que recubre el interior de las paredes alveolares y funciona como agente tensioactivo. Caso clínico: Recién nacido a término que presentó dificultad respiratoria a los 3 días de vida y requirió ventilación mecánica. Los estudios para determinar otras causas de enfermedad pulmonar fueron negativos. Se realizó una biopsia de pulmón para realizar estudios de microscopía óptica y microscopía electrónica. Esta última mostró pequeños cuerpos lamelares anómalos, además de condensaciones electrodensas periféricas, características de las mutaciones del transportador ABCA3. Se inició tratamiento con pulsos de metilprednisolona, hidroxicloroquina, azitromicina y corticoides inhalados a dosis altas, y la respuesta clínica y radiológica fue favorable durante el seguimiento. Conclusiones: La correlación de las características clínicas y de las imágenes (tomografía y microscopía electrónica) puede ser útil para el diagnóstico de la disfunción del surfactante pulmonar, especialmente en los países de bajos y medianos recursos que no disponen de estudios genéticos para determinar las diferentes mutaciones del transportador ABCA3. Este es uno de los primeros casos reportados en Perú con respuesta adecuada al tratamiento y evolución favorable durante el seguimiento.

Abstract Background: Genetic disorders affecting pulmonary surfactant homeostasis are a major cause of respiratory distress syndrome in full-term newborn and childhood interstitial lung disease. The ABCA3 transporter (ATP binding cassette A3) intervenes in the normal production of surfactant that covers the interior of alveolar walls and plays a fundamental role as a surfactant. Case report: Male term newborn who presented respiratory distress 3 days after birth and required mechanical ventilation. Studies to determine other causes of lung disease were negative. Lung biopsy was performed for the study with light microscopy and electron microscopy. Electron microscopy showed small abnormal lamellar bodies in addition to peripheral electrodense condensations characteristic of ABCA3 transporter mutation. Treatment was started with pulses of methylprednisolone, hydroxychloroquine, azithromycin, and high-dose inhaled corticosteroids, finding a favorable clinical and radiological response to follow-up. Conclusions: Correlation of clinical characteristics and images (tomography and electron microscopy) can be useful for the diagnosis of lung surfactant dysfunction, especially in low and medium-income countries where genetic studies to determine the different ABCA3 transporter mutations are not available. This is one of the first cases reported in Peru with an adequate response to treatment and favorable evolution to follow-up.

The biology, function, and applications of exosomes in cancer

Exosomes are cell-derived nanovesicles with diameters from 30 to 150 nm, released upon fusion of multivesicular bodies with the cell surface. They can transport nucleic acids, proteins, and lipids for intercellular communication and activate signaling pathways in target cells. In cancers, exosomes may participate in growth and metastasis of tumors by regulating the immune response, blocking the epithelial-mesenchymal transition, and promoting angiogenesis. They are also involved in the development of resistance to chemotherapeutic drugs. Exosomes in liquid biopsies can be used as non-invasive biomarkers for early detection and diagnosis of cancers. Because of their amphipathic structure, exosomes are natural drug delivery vehicles for cancer therapy.

Study on the relationship between synonymous mutation of ABCA3 gene and neonatal respiratory distress syndrome of mongolian and han nationality in inner mongolia / 中华急诊医学杂志

Objective:To investigate whether the synonymous variation of the ATP-binding cassette transporter A3 (ABCA3) gene may increase the risk of respiratory distress syndrome (RDS) in Mongolian and Han newborns in Inner Mongolia.Methods:From January 2018 to June 2019, the children of Mongolian and Han nationality who were hospitalized in the Department of Neonatal Pediatrics, affiliated Hospital of Inner Mongolia Medical University and the control group were sequenced by ABCA3 exon gene to analyze whether there was synonymous mutation in ABCA3 gene.Results:A total of 101 children with RDS were enrolled, including 37 children with Mongolian and 64 with Han children. There were 113 patients in the control group, including 45 Mongolian children and 68 Han children. Children with Mongolian and Han nationality RDS and control group can detect multiple synonymous mutation sites, such as: F353F, P585P, A227A, V150V, L982L, A928A, S1372S, P1653P, E1618E, and A1027A, etc, among them, four synonymous variants of p.A227A, p.F353F, p.P585P and p.S1372S are common synonymous mutants. In both Mongolian and Han nationality, the frequency of ABCA3 gene synonymous mutation in RDS group was significantly higher than that in control group (Mongolian: χ2=9.402, P=0.002; Han: χ2=9.348, P=0.002 ). The mutation rates of F353F and P585P in Mongolian and Han children with RDS were higher than those in the control group, and the difference was statistically significant(Mongolian F353F: χ2=5.270, P=0.022; Han F353F: χ2=5.532, P=0.019.Mongolian P585P: χ2=4.711, P=0.030; Han P585P: χ2=4.480, P=0.034). Conclusions:The synonymous variation of ABCA3 gene may increase the risk of RDS in Mongolian and Han newborns in Inner Mongolia, and F353F and P585P may be one of the susceptible genes of RDS in Mongolian and Han newborns in Inner Mongolia.

El intersticio pulmonar y sus enfermedades en la infancia. Deficiencia de ABCA3. Seguimiento durante doce años. Perspectivas ¿Un nuevo paradigma genético? / The pulmonary interstitium and its diseases in childhood. ABCA3 deficiency. Follow-up for 12 years. Perspectives. A new genetic paradigm?

Introducción. Sobre la base de un caso clínico, se presenta la descripción del cuadro intersticial por deficiencia de ABCA3, de una paciente de catorce años de edad, en seguimiento durante doce años. Método. Evaluación clínica con extensos estudios para descartar otras patologías semejantes. El diagnóstico definitivo fue determinado por el estudio genético para deficiencias de ABCA3 y otros defectos genéticos realizados por el Dr. Larry Nogee, Hospital Johns Hopkins, EE. UU. Objetivos. Describir detalladamente la evolución de la paciente durante doce años, con énfasis en los estudios anteriormente mencionados. Sugerir la presencia de un cambio de paradigma pronóstico en lo que se conocía sobre la evolución de esta enfermedad intersticial pulmonar grave, tratar de mejorar la calidad de vida y posiblemente el pronóstico. Presentar los hallazgos de genética, anatomía patológica y radiología en consultas y evaluaciones por centros de referencia. Resultados. Realizado su diagnóstico de deficiencia genética de ABCA3, presentamos su seguimiento actualizado hasta el año 2020. Esta debe ser sospechada en niños pequeños desde el nacimiento y durante los primeros años ante la persistencia de cuadros pulmonares crónicos con desaturación de oxígeno e imágenes tomográficas que sugieren cuadro intersticial. Se decidió tratar el cuadro en los años 2019-2020, durante seis meses, según bibliografía y consultas con centros de referencia en los Estados Unidos, con la finalidad de determinar la posible mejoría de su patología y decidir la continuación o suspensión de la medicación. Se usaron pulsos con metilprednisolona- hidroxicloroquina y azitromicina. Se logró mantener estable su función pulmonar y mejorar notablemente su calidad de vida. (AU)

Introduction. A clinical case diagnosed with ABCA3 deficiency is described. Patient is now fourteen years old. She´s being followed up since she was two years old. Methodology. clinical follow ­ up with extensive studies to rule out other similar pathologies. Final diagnosis was done through genetic studies done at Johns Hopkins Hospital by Nogee LM. Objective. To present a detailed evolution description of twelve years' follow-up with the support of the aforementioned studies, to suggest a change in diagnostic ­ prognostic paradigm on what was known of mortality in this severe pulmonary interstitial pathology to improve life quality and possibly prognosis. Present the findings of genetics, pathological anatomy and radiology in consultations and evaluations by reference centers. Results. Having made her diagnosis of genetic ABCA3 deficiency, we present her up dated follow-up until 2020. This should be suspected in young children from birth and during the first years due to the persistence of chronic pulmonary symptoms with oxygen desaturation and tomographic images that suggest interstitial symptoms. It was decided to treat the condition in the years 2019-2020, for six months, according to the bibliography and consultations with reference centers in the United States, in order to determine the possible improvement of her pathology and decide to continue or suspend the medication. Pulses with methylprednisolone hydroxychloroquine and azithromycin were used. Her lung function was stable and her quality of life significantly improved. (AU)

Correlation between ABCA3 and Pediatric Pulmonary Disease / 临床儿科杂志

Pulmonary surfactant is a lipid-protein complex that lines and stabilizes the respiratory interface in the alveoli, allowing for gas exchange during the breathing cycle. ATP-binding Cassette transporters A3, is a lipid transporter in the limiting membrane of lamellar bodies in alveolar type Ⅱ cells that plays a critical role in the regulation of pulmonary surfactant homeostasis. Mutations in the ABCA3 gene cause respiratory distress syndrome in new-born and childhood interstitial lung disease. An updated view on expression of ABCA3 gene and ABCA3 mutation associated with neonatal respiratory distress syndrome,or childhood interstitial lung disease was reviewed.

A novel compound heterozygous mutation in ABCA3 gene in a child with diffuse parenchymal lung disease / 中华儿科杂志

Objective@#To summarize the clinical characteristics of the diffuse parenchymal lung diseases in a child caused by a novel compound heterozygous ABCA3 mutation and explore the association between the phenotype and ABCA3 mutation.@*Method@#The clinical material of a patient diagnosed with diffuse parenchymal lung disease with ABCA3 mutation in December 2016 in Shenzhen Children's Hospital was analyzed. The information about ABCA3 gene mutation updated before April, 2017 was searched and collected from the gene databases (including 1000Genomes, HGMD, EXAC) and the literatures (including Wanfang Chinese database and Pubmed).@*Result@#The girl was one year and nine months old. She presented with chronic cough, tachypnea, cyanosis and failure to thrive since she was one year and three months old. Her condition gradually deteriorated after she was empirically treated. Physical examination showed malnutrition, tachypnea and clubbed-fingers. Her high resolution computed tomography (HRCT) revealed diffused ground-glass opacities, thickened interlobular septum, and multiple subpleural small air-filled lung cysts. The second generation sequencing study identified a novel compound heterozygous mutation (c.1755delC+c.2890G>A) in her ABCA3 gene, which derived respectively from her parents and has not been reported in the database and the literatures mentioned above.@*Conclusion@#c.1755delC+c.2890G>A is a new kind of compound heterozygous mutation in ABCA3, which can cause children's diffuse parenchymal lung disease. Its phenotype is related to its genotype.

Relationship between ABCA3 gene polymorphisms and susceptibility with neonatal respiratory distress syndrome / 中国小儿急救医学

Objective To investigate ABCA3 gene polymorphism and its relationship with neonatal respiratory distress syndrome (NRDS) in the Guangxi Zhuang Autonomous Region of China by genotyping and haplotype analysis.Methods Using a tagging single nucleotide polymorphism (tSNP) strategy and TaqMan (r) real-time PCR,we genotyped 4 tSNPs (rs4787273,rs 1 50929,rs 11867129,and rs 17135889) and one additional coding SNP(rs13332514) of the ABCA3 gene in preterm infants with NRDS(NRDS group,n =45) and without NRDS (non-NRDS group,n =45) and subsequently predicted the haplotypes.The minor allele frequency and the haplotype 'distribution were compared between the two groups.Results The minor allele A(0.14 vs.0.05,P =0.046) and genotype AG (0.289 vs.0.111,P =0.035) frequency of SNP rs17135889 in NRDS group were significantly higher than those in non-NRDS group.Totally 6 haplotypes occurred at a frequency ≥0.01,among which,the haplotype TGGAG,depended on rs17135889,was significantly higher in NRDS group than that in non-NRDS group (0.061 vs.0.000,P =0.014).Conclusion The results suggested that SNP rs17135889 of ABCA3 gene might be related to NRDS in preterm population of the Guangxi Zhuang Autonomous Region.Allele A contributes to NRDS susceptibility in preterm infants.

Impact of High ABCA3 Expression in Nasopharyngeal Carcinoma Stem Cells on theResistance to Cisplatin / 医药导报

Objective To investigate the role of ATP￣binding cassette ( ABC ) family on the resistance of nasopharyngeal carcinoma (NPC) stem cells (CSCs) to cisplatin. Methods We compared the differences between the drug extravasation capability of CNE￣2 and CNE￣2S by using Rhodamine￣123 efflux assay. We determined the mRNA and protein expression levels of ABC transport family members, including ABCA3,ABCB1,ABCB5,ABCC1,ABCC2 and ABCG2,after 48 h being treated with 1 μmol.L-1 cisplatin by RT￣PC and Western blotting.Rhoamine￣123 efflux and apoptosis by cisplatin in two kinds of cells was examined by ABCA3 gene silencing with specific small￣interfering RNA. Results The IC50 of cisplatin on CNE￣2S was 4.1 fold to that on CNE￣2(P<0.05).For the relative drug effluent activity and Na+K+ ATPase activity,CNE￣2S was 4.8 fold to CNE￣2(P<0.05),suggested that CNE￣2S expressed more ABCA3,ABCB1,ABCC1 and ABCG2 in comparison to CNE￣2(P<0.05).After 48 h treatment with 1 μmol.L-1 cisplatin,ABCA3 specifically highly expressed in CNE￣2S (P<0.05), and knocking down of ABCA3 resulted in reduction of rhodamine￣123 efflux and increase of apoptosis. Conclusion The cisplatin resistance of NPC CSCs is associated with enhanced expression of ABCA3,ABCC1 and ABCG2, suppression of ABCA3 could reverse the resistance of NPC CSCs to cisplatin.