Variants of the ABCA3 gene might contribute to susceptibility to interstitial lung diseases in the Chinese population

Zhou, Wei; Yi, Zichuan; Sun, Jiapeng; Wang, Xiaofen; Zhao, Q.; Xu, Lizhi; Wang, Yaping

doi:10.1038/s41598-017-04486-y

Cited by 18 publications

(9 citation statements)

References 40 publications

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“…However, heterozygous ABCA3 mutations have also been associated with an increased risk of neonatal respiratory distress in late preterm newborns. The increasing number of mutations docu-mented in a heterozygous state suggests that ABCA3 defects may be the most common causes of inherited surfactant diseases [78]. To date, more than 200 mutations have been reported in ABCA3, located on chromosome 16, with various heterogeneous clinical expressions, even in siblings [79][80][81].…”

Section: Genetic Disorders Of Surfactant Metabolismmentioning

confidence: 99%

Chronic interstitial lung diseases in children: diagnosis approaches

Nathan

Berdah

Borensztajn

et al. 2018

Expert Review of Respiratory Medicine

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HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

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Section: Genetic Disorders Of Surfactant Metabolismmentioning

confidence: 99%

Chronic interstitial lung diseases in children: diagnosis approaches

Nathan

Berdah

Borensztajn

et al. 2018

Expert Review of Respiratory Medicine

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“…Patients with two severe mutations (null or loss of function) present early and die or are transplanted within a year of birth [ 22 ]. ABCA3 mutations may be the commonest inherited SP abnormality [ 23 ].…”

Section: Aetiologymentioning

confidence: 99%

Pulmonary alveolar proteinosis in children

Bush

Pabary

2020

Breathe

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Pulmonary alveolar proteinosis (PAP) is an umbrella term for a wide spectrum of conditions that have a very characteristic appearance on computed tomography. There is outlining of the secondary pulmonary lobules on the background of ground-glass shadowing and pathologically, filling of the alveolar spaces with normal or abnormal surfactant. PAP is rare and the common causes in children are very different from those seen in adults; autoimmune PAP is rare and macrophage blockade not described in children. There are many genetic causes of PAP, the best known of which are mutations in the genes encoding surfactant protein (SP)-B, SP-C, thyroid transcription factor 1, ATP-binding cassette protein 3, and the granulocyte–macrophage colony-stimulating factor (GM-CSF) receptor α- and β- chains. PAP may also be a manifestation of rheumatological and metabolic disease, congenital immunodeficiency, and haematological malignancy. Precise diagnosis of the underlying cause is essential in planning treatment, as well as for genetic counselling. The evidence base for treatment is poor. Some forms of PAP respond well to whole-lung lavage, and autoimmune PAP, which is much commoner in adults, responds to inhaled or subcutaneous GM-CSF. Emerging therapies based on studies in murine models of PAP include stem-cell transplantation for GM-CSF receptor mutations.Educational aimsTo understand when to suspect that a child has pulmonary alveolar proteinosis (PAP) and how to confirm that this is the cause of the presentation.To show that PAP is an umbrella term for conditions characterised by alveolar filling by normal or abnormal surfactant, and that this term is the start, not the end, of the diagnostic journey.To review the developmental differences in the spectrum of conditions that may cause PAP, and specifically to understand the differences between causes in adults and children.To discuss when to treat PAP with whole-lung lavage and/or granulocyte–macrophage colony-stimulating factor, and review potential promising new therapies.

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“…It maintains effective ventilation in the lungs by reducing the surface tension in the alveoli [ 1 ]. ABCA3 (The adenosine triphosphate (ATP) binding cassette subfamily A, member 3) hydrolyzes ATP to transport phospholipids which combine with surfactant proteins to yield pulmonary surfactant [ 2 , 3 ].…”

Section: Introductionmentioning

confidence: 99%

A novel synonymous ABCA3 variant identified in a Chinese family with lethal neonatal respiratory failure

Zhang¹,

Li²,

Lin³

et al. 2021

BMC Med Genomics

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Background Lethal respiratory failure is primarily caused by a deficiency of pulmonary surfactant, and is the main cause of neonatal death among preterm infants. Pulmonary surfactant metabolism dysfunction caused by variants in the ABCA3 gene is a rare disease with very poor prognosis. Currently, the mechanisms associated with some ABCA3 variants have been determined, including protein mistrafficking and impaired phospholipid transport. However, some novel variants and their underlying pathogenesis has not been fully elucidated yet. In this study we aimed to identify the genetic features in a family with lethal respiratory failure. Methods We studied members of two generations of a Chinese family, including a female proband, her parents, her monozygotic twin sister, and her older sister. Trio whole exome sequencing (WES) were used on the proband and her parents to identify the ABCA3 variants. Sanger sequencing and real-time quantitative polymerase chain reaction (PCR) were used on the monozygotic twin sister of proband to validate the ABCA3 synonymous variant and exon deletion, respectively. The potential pathogenicity of the identified synonymous variant was predicted using the splice site algorithms dbscSNV11_AdaBoost, dbscSNV11_RandomForest, and Human Splicing Finder (HSF). Results All patients showed severe respiratory distress, which could not be relieved by mechanical ventilation, supplementation of surfactant, or steroid therapy, and died at an early age. WES analysis revealed that the proband had compound heterozygous ABCA3 variants, including a novel synonymous variant c.G873A (p.Lys291Lys) in exon 8 inherited from the mother, and a heterozygous deletion of exons 4–7 inherited from the father. The synonymous variant was consistently predicted to be a cryptic splice donor site that may lead to aberrant splicing of the pre-mRNA by three different splice site algorithms. The deletion of exons 4–7 of the ABCA3 gene was determined to be a likely pathogenic variant. The variants were confirmed in the monozygotic twin sister of proband by Sanger sequencing and qPCR respectively. The older sister of proband was not available to determine if she also carried both ABCA3 variants, but it is highly likely based on her clinical course. Conclusions We identified a novel synonymous variant and a deletion in the ABCA3 gene that may be responsible for the pathogenesis in patients in this family. These results add to the known mutational spectrum of the ABCA3 gene. The study of ABCA3 variants may be helpful for the implementation of patient-specific therapies.

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Variants of the ABCA3 gene might contribute to susceptibility to interstitial lung diseases in the Chinese population

Cited by 18 publications

References 40 publications

Chronic interstitial lung diseases in children: diagnosis approaches

Chronic interstitial lung diseases in children: diagnosis approaches

Pulmonary alveolar proteinosis in children

A novel synonymous ABCA3 variant identified in a Chinese family with lethal neonatal respiratory failure

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