Increased Risk of Interstitial Lung Disease in Children with a Single R288K Variant of ABCA3

Wittmann, Thomas; Frixel, Sabrina; Höppner, Stefanie; Schindlbeck, Ulrike; Schams, Andrea; Kappler, Matthias; Hegermann, Jan; Wrede, Christoph; Liebisch, Gerhard; Vierzig, Anne; Zacharasiewicz, Angela; Kopp, Matthias; Poets, Christian F.; Baden, Winfried; Hartl, Dominik; Kaam, Anton H. van; Aslanidis, Charalampos; Zarbock, Ralf; Griese, Matthias

doi:10.2119/molmed.2015.00244

Cited by 21 publications

(29 citation statements)

References 34 publications

(46 reference statements)

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“…() described the case of a girl, homozygously expressing the p.G964D variant, who was diagnosed with usual interstitial pneumonia fairly late in her youth. A group of children carrying the p.R288K variant in a heterozygous manner all presented with neonatal respiratory insufficiency and developed chronic ILD during their early childhood (Wittmann et al., ). As reported above, a newborn heterozygous for the mutations p.M760R and p.R208W also experienced early respiratory failure, indicating that the variant p.R208W was not capable to compensate for the heavy trafficking defect encoded by the p.M760R variant on the other allele (Doan et al., ).…”

Section: Discussionmentioning

confidence: 99%

“…Based on these clinical observations, we think that the variants p.R208W, p.R288K, and p.G964D predispose for the development of ILD by yet undefined mechanisms that cannot be classified into neither type 1 nor type 2 mutations. The underlying pathologies of these variations appear to be less severe, but the possible combination with previous initial lung injury (Kaltenborn et al., ; Wittmann et al., ) or a longer time span during which interstitial injury and fibrosis might arise (Campo et al., ) may result in chronic ILD. Such differences are also more difficult to detect.…”

Section: Discussionmentioning

confidence: 99%

“…Unfortunately, clinical data and in particular lung tissue or molecular investigations are not always available. In order to gain insight into the cellular phenotype, we developed a number of tools to assess cellular pathologies related to ABCA3 mutations in a previous study, where we could demonstrate close correlations between in vitro results and ex vivo data (Brasch et al., ; Campo et al., ; Wittmann et al., ; Wittmann et al., ).…”

Section: Introductionmentioning

confidence: 99%

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ABCA3 missense mutations causing surfactant dysfunction disorders have distinct cellular phenotypes

Schindlbeck¹,

Wittmann²,

Höppner³

et al. 2018

Human Mutation

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Mutations in the ATP-binding cassette subfamily A member 3 (ABCA3) gene are the most common monogenetic cause of surfactant dysfunction disorders in newborns and interstitial lung diseases in children and young adults. Although the effect of mutations resulting in truncated or incomplete proteins can be predicted, the consequences of missense variants cannot be as easily. Our aim was to investigate the intracellular handling and disturbance of the cellular surfactant system in a stable cell model with several different clinically relevant ABCA3 missense mutations. We found that the investigated missense mutations within the ABCA3 gene affect surfactant homeostasis in different ways: first by disrupting intracellular ABCA3 protein localization (c.643C > A, p.Q215K; c.2279T > G, p.M760R), second by impairing the lipid transport of ABCA3 protein (c.875A > T, p.E292V; c.4164G > C, p.K1388N), and third by yet undetermined mechanisms predisposing for the development of interstitial lung diseases despite correct localization and normal lipid transport of the variant ABCA3 protein (c.622C > T, p.R208W; c.863G > A, p.R288K; c.2891G > A, p.G964D). In conclusion, we classified cellular consequences of missense ABCA3 sequence variations leading to pulmonary disease of variable severity. The corresponding molecular pathomechanisms of such ABCA3 variants may specifically be addressed by targeted treatments.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

ABCA3 missense mutations causing surfactant dysfunction disorders have distinct cellular phenotypes

Schindlbeck¹,

Wittmann²,

Höppner³

et al. 2018

Human Mutation

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“…At birth, all had neonatal respiratory distress, recovered and developed chronic ILD with intermittent exacerbations during early childhood. Detailed analysis of the R288K variant in ABCA3 showed smaller lamellar bodies and a reduced dipalmitoyl-phosphatidylcholine content and decreased lamellar body volume of the cells studied [26]. It was suggested that the heterozygous R288K variant can underlie ILD in childhood as a significant risk factor.…”

Section: Dpld Group A4: Ild Related To Alveolar Surfactant Regionmentioning

confidence: 92%

“…These variations were either present in a homozygous or compound heterozygous arrangement, as expected for an autosomal recessive condition. In addition, heterozygous mutations in ABCA3, such as R288K have been associated with increased rates of neonatal respiratory distress [25] or ILD in older children [26]. In a retrospective cohort study of 228 children with ILD related to the alveolar surfactant system, nine children with ILD carrying a single (heterozygous) R288K variant, a frequency significantly higher than in the general Caucasian population, were found.…”

Section: Dpld Group A4: Ild Related To Alveolar Surfactant Regionmentioning

confidence: 99%

Chronic interstitial lung disease in children

Griese

2018

Eur Respir Rev

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Children's interstitial lung diseases (chILD) are increasingly recognised and contain many lung developmental and genetic disorders not yet identified in adult pneumology. Worldwide, several registers have been established. The Australasian Registry Network for Orphan Lung Disease (ARNOLD) has identified problems in estimating rare disease prevalence; focusing on chILD in immunocompetent patients, a period prevalence of 1.5 cases per million children and a mortality rate of 7% were determined. The chILD-EU register highlighted the workload to be covered per patient included and provided protocols for diagnosis and initial treatment, similar to the United States chILD network. Whereas case reports may be useful for young physicians to practise writing articles, cohorts of patients can catapult progress, as demonstrated by recent studies on persistent tachypnoea of infancy, hypersensitivity pneumonitis in children and interstitial lung disease related to interferonopathies from mutations in transmembrane protein 173. Translational research has linked heterozygous mutations in the ABCA3 transporter to an increased risk of interstitial lung diseases, not only in neonates, but also in older children and adults. For surfactant dysfunction disorders in infancy and early childhood, lung transplantation was reported to be as successful as in adult patients. Mutual potentiation of paediatric and adult pneumologists is mandatory in this rapidly extending field for successful future development.

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Interstitial lung disease in children with Rubinstein‐Taybi syndrome

Bradford

Ross

Minso

et al. 2021

Pediatric Pulmonology

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Introduction Rubinstein‐Taybi syndrome (RSTS) is a rare genetic syndrome caused primarily by a mutation in the CREBBP gene found on chromosome 16. Patients with RSTS are at greater risk for a variety of medical problems, including upper airway obstruction and aspiration. Childhood interstitial lung disease (ILD) thus far has not been definitively linked to RSTS. Here we present three patients with RSTS who developed ILD and discuss possible mechanisms by which a mutation in CREBBP may be involved in the development of ILD. Methods Routine hematoxylin and eosin staining was performed on lung biopsy tissue for histological analysis. Immunofluorescent staining was performed on lung biopsy tissue for markers of fibrosis, surfactant deficiency and histone acetylation. Cases 1 and 2 had standard clinical microarray analysis. Case 3 had whole exome sequencing. Bioinformatics analyses were performed to identify possible causative genes using ToppGene. Results Computed tomography images in all cases showed consolidated densities overlying ground glass opacities. Lung histopathology revealed accumulation of proteinaceous material within alveolar spaces, evidence of fibrosis, and increased alveolar macrophages. Immunofluorescent staining showed increase in surfactant protein C staining, patchy areas of increased anti‐smooth muscle antibody staining, and increased staining for acetylated histone 2 and histone 3 lysine 9. Discussion Clinical characteristics, radiographic imaging, lung histopathology, and immunofluorescent staining results shared by all cases demonstrated findings consistent with ILD. Immunofluorescent staining suggests two possible mechanisms for the development of ILD: abnormal surfactant metabolism and/or persistent activation of myofibroblasts. These two pathways could be related to dysfunctional CREBBP protein.

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Increased Risk of Interstitial Lung Disease in Children with a Single R288K Variant of ABCA3

Cited by 21 publications

References 34 publications

ABCA3 missense mutations causing surfactant dysfunction disorders have distinct cellular phenotypes

ABCA3 missense mutations causing surfactant dysfunction disorders have distinct cellular phenotypes

Chronic interstitial lung disease in children

Interstitial lung disease in children with Rubinstein‐Taybi syndrome

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