Novel ABCA3 mutations as a cause of respiratory distress in a term newborn

Jm, Gonçalves; Pinheiro, Liliana; Costa, Miguel; Silva, Albina; Gonçalves, Augusta; Pereira, Almerinda

doi:10.1016/j.gene.2013.11.015

Cited by 22 publications

(20 citation statements)

References 25 publications

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“…Many of these mutations are clustered within the first and forth luminal loops as well as in the cytosolic domains, particularly within or adjacent to the second nucleotide-binding domain (NBD2). As previously stated, the presence of a combination of Type I (trafficking) and Type II (lipid pump) variants as compound heterozygous mutations appears to increase the disease severity in children as evidenced by the parents of these children having only one of the mutations and being asymptomatic without apparent respiratory disease (Kitazawa et al, 2013; Wambach et al, 2014; Flamein et al, 2012; Goncalves et al, 2014; Kitazawa and Kure, 2015). While ABCA3 -associated lung disease is believed to be inherited in an autosomal recessive manner requiring mutations on both alleles, monoallelic ABCA3 mutations in infants with surfactant deficiency and in children and adults with IPF/DPLD are also common (Shulenin et al, 2004; Agrawal et al, 2012; Peca et al, 2015; Wambach et al, 2012; Naderi et al, 2014).…”

Section: The Role Of Compound Heterozygous Mutations In Abca3 Mediatementioning

confidence: 89%

“…Similarly, as Figure 3 schematically illustrates, over 200 distinct ABCA3 mutations have been identified and are recognized as the most prevalent group of mutations among genes associated with surfactant related lung disorders (Shulenin et al, 2004; Ota et al, 2016; Peca et al, 2015; Bullard et al, 2005; Garmany et al, 2006; Doan et al, 2008; Flamein et al, 2012; Wambach et al, 2014; Goncalves et al, 2014). Various types of coding and non-coding variants in the ABCA3 gene have been described including missense, nonsense, frameshift, insertion, deletion, and splice site mutations.…”

Section: Abca3 Mutations Are Associated With Pulmonary Disordersmentioning

confidence: 99%

“…As illustrated in Figure 3, compound heterozygous variants account for approximately three quarters of all report lung disease-associated ABCA3 mutations to date (Shulenin et al, 2004; Matsumura et al, 2008; Ota et al, 2016; Peca et al, 2015; Bullard et al, 2005; Garmany et al, 2006; Doan et al, 2008; Flamein et al, 2012; Wambach et al, 2014; Goncalves et al, 2014). Many of these mutations are clustered within the first and forth luminal loops as well as in the cytosolic domains, particularly within or adjacent to the second nucleotide-binding domain (NBD2).…”

Section: The Role Of Compound Heterozygous Mutations In Abca3 Mediatementioning

confidence: 99%

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The biology of the ABCA3 lipid transporter in lung health and disease

Beers

Mulugeta

2016

Cell Tissue Res

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The lipid transporter, ATP binding cassette, class A3 (ABCA3) is a highly conserved multi-membrane spanning protein that plays a critical role in the regulation of pulmonary surfactant homeostasis. Mutations in ABCA3 have been increasingly recognized as one of the causes of inherited pulmonary diseases. These monogenic disorders produce familial lung abnormalities with pathological presentations ranging from neonatal surfactant deficiency-induced respiratory failure to childhood or adult diffuse parenchymal lung diseases for which specific treatment modalities remain quite limited. More than 200 ABCA3 mutations have been reported to date with approximately three quarters of patients presenting as compound heterozygotes. Recent advances in our understanding of the molecular basis underlying normal ABCA3 biosynthesis and processing, as well as the mechanisms of alveolar epithelial cell dysregulation caused by the expression of its mutant forms, are beginning to emerge. These insights, as well as the role of environmental factors and modifier genes, are discussed in the context of the considerable variability in disease presentation observed in patients with identical ABCA3 gene mutations. Moreover, the opportunities afforded by an enhanced understanding of ABCA3 biology for targeted therapeutic strategies are addressed.

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Section: The Role Of Compound Heterozygous Mutations In Abca3 Mediatementioning

confidence: 89%

Section: Abca3 Mutations Are Associated With Pulmonary Disordersmentioning

confidence: 99%

Section: The Role Of Compound Heterozygous Mutations In Abca3 Mediatementioning

confidence: 99%

See 1 more Smart Citation

The biology of the ABCA3 lipid transporter in lung health and disease

Beers

Mulugeta

2016

Cell Tissue Res

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“…2013 [ 9 ] Newborn, mild respiratory distress syndrome c.447 + 11C>T c.2333 A>G Family history of sibling with fatal respiratory distress syndrome, lung histopathology, and electron microscopy Alive Four variants for ABCA3 c.4583 C>T c.3755 T>C Gonçalves et al . 2013 [ 10 ] Newborn, respiratory distress syndrome L798P R1612P Lung histology Died Compound heterozygous mutations in ABCA3 Panigrahy et al . 2014 [ 11 ] Newborn, respiratory distress syndrome c3703 + 1 G>T c3703 + 1 G>T Lung histology Died Homozygous for ABCA3 Malý et al .…”

Section: Discussionmentioning

confidence: 99%

Fatal respiratory disease due to a homozygous intronic ABCA3 mutation: a case report

et al. 2016

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BackgroundPulmonary surfactant is a complex mixture of lipids and proteins. Mutations in surfactant protein-C, surfactant protein-D, and adenosine triphosphate-binding cassette subfamily A member 3 have been related to surfactant dysfunction and neonatal respiratory failure in full-term babies. Adenosine triphosphate-binding cassette subfamily A member 3 facilitates the transfer of lipids to lamellar bodies. We report the case of patient with a homozygous intronic ABCA3 mutation.Case presentationWe describe a newborn full-term Colombian baby boy who was the son of non-consanguineous parents of mixed race ancestry (Mestizo), who was delivered with severe respiratory depression. Invasive treatment was unsuccessful and diagnosis was uncertain. Exons 4 and 5 of the SP-C gene showed heterozygous Thr138Asn polymorphism and homozygous Asn186Asn polymorphism respectively. At intron 25 at position –98 from exon 26 a homozygous C>T transition mutation was detected in ABCA3 gene.ConclusionsThe clinical presentation and the histopathological findings of this case are consistent with a case of neonatal respiratory failure due to surfactant deficiency. Analysis of the five coding SP-C exons does not support surfactant deficiency. An analysis of the mutation IVS25-98 T was performed and a homozygous mutation responsible for our case’s neonatal respiratory failure was detected. The findings suggest an autosomic recessive pattern of inheritance. Genetic counseling was provided and the relatives are now informed of the recurrence risks and treatment options.

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“…It has become increasingly evident that there are additional cis - and trans -allelic mutations within ABCA3 gene that can act as disease modifiers (Bullard and Nogee, 2007; Kitazawa et al, 2013; Flamein et al, 2012; Goncalves et al, 2014; Beers and Mulugeta, 2016). Several reports have identified patients suffering from chronic lung disorders (with diagnoses of various types of DPLD including pulmonary fibrosis) that carry compound heterozygous mutations (Bullard et al, 2005; Bullard and Nogee, 2007; Kitazawa et al, 2013; Flamein et al, 2012) or an accompanying SFTPC mutation mutations (Bullard and Nogee, 2007; Crossno et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Aberrant lung remodeling in a mouse model of surfactant dysregulation induced by modulation of the Abca3 gene

Beers

Knudsen

Tomer

et al. 2017

Annals of Anatomy - Anatomischer Anzeiger

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The lipid transporter, ATP binding cassette class A3 (ABCA3), plays a critical role in the biogenesis of alveolar type 2 (AT2) cell lamellar bodies (LBs). A relatively large number of mutations in the ABCA3 gene have been identified in association with diffuse parenchymal lung disease (DPLD), the most common of which is a missense mutation (valine substitution for lysine at residue 292 (ABCA3 E292V )) that leads to functional impairment of the transporter in vitro. The consequences of ABCA3 E292V gene expression in vivo are unknown. To address this question, we developed mouse models expressing ABCA3 E292V knocked-in to the endogenous mouse locus. The parental (F1) mouse line (mAbca3 E292V ) that retained an intronic pgk-Neo selection cassette (inserted in reverse orientation) (mAbca3 E292V -rNeo) demonstrated an allele dependent extracellular surfactant phospholipid (PL) deficiency. We hypothesize that this PL deficiency leads to aberrant parenchymal remodeling contributing to the pathophysiology of the DPLD phenotype. Compared to wild type littermates, baseline studies of mice homozygous for the pgk-Neo insert (mAbca3 E292V -rNeo +/+ ) revealed nearly 50% reduction in bronchoalveolar lavage (BAL) PL content that was accompanied by quantitative reduction in AT2 LB size with a compensatory increase in LB number. The phenotypic alteration in surfactant lipid homeostasis resulted in an early macrophage predominant alveolitis which peaked at 8 weeks of age. This was followed by age-dependent development of histological DPLD characterized initially by peribronchial inflammatory cell infiltration and culminating in both an emphysema-like phenotype (which included stereologically quantifiable reductions in both alveolar septal surface area and volume of septal wall tissue) plus foci of trichrome-positive collagen deposition together with substantial proliferation of hyperplastic AT2 cells. In addition to spontaneous lung remodeling, mABCA3 E292V -rNeo mice were rendered more vulnerable to exogenous injury. Three weeks ✩ This paper belongs to the special issue surfactants and surface activity. HHS Public Access

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Novel ABCA3 mutations as a cause of respiratory distress in a term newborn

Cited by 22 publications

References 25 publications

The biology of the ABCA3 lipid transporter in lung health and disease

The biology of the ABCA3 lipid transporter in lung health and disease

Fatal respiratory disease due to a homozygous intronic ABCA3 mutation: a case report

Aberrant lung remodeling in a mouse model of surfactant dysregulation induced by modulation of the Abca3 gene

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