Structure-Based Understanding of ABCA3 Variants

Onnée, Marion; Fanen, Pascale; Callebaut, Isabelle; Becdelièvre, Alix de

doi:10.3390/ijms221910282

Cited by 9 publications

(8 citation statements)

References 42 publications

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“…Variants plotted in blue: carrier survived beyond 1 year; plotted in orange: patients’ death before 1 year; edged yellow or blue dots: homozygous variants; dots with asterisk: compound heterozygous mutations. The position of TMDs and NBDs of ABCA3 were referred to the prediction algorithms of Onnée et al 40. (B).…”

Section: Resultsmentioning

confidence: 99%

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ABCA3-related interstitial lung disease beyond infancy

Seidl

Knoflach

et al. 2023

Thorax

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BackgroundThe majority of patients with childhood interstitial lung disease (chILD) caused by pathogenic variants in ATP binding cassette subfamily A member 3 (ABCA3) develop severe respiratory insufficiency within their first year of life and succumb to disease if not lung transplanted. This register-based cohort study reviews patients with ABCA3 lung disease who survived beyond the age of 1 year.MethodOver a 21-year period, patients diagnosed as chILD due to ABCA3 deficiency were identified from the Kids Lung Register database. 44 patients survived beyond the first year of life and their long-term clinical course, oxygen supplementation and pulmonary function were reviewed. Chest CT and histopathology were scored blindly.ResultsAt the end of the observation period, median age was 6.3 years (IQR: 2.8–11.7) and 36/44 (82%) were still alive without transplantation. Patients who had never received supplemental oxygen therapy survived longer than those persistently required oxygen supplementation (9.7 (95% CI 6.7 to 27.7) vs 3.0 years (95% CI 1.5 to 5.0), p=0.0126). Interstitial lung disease was clearly progressive over time based on lung function (forced vital capacity % predicted absolute loss −1.1% /year) and on chest CT (increasing cystic lesions in those with repetitive imaging). Lung histology pattern were variable (chronic pneumonitis of infancy, non-specific interstitial pneumonia, and desquamative interstitial pneumonia). In 37/44 subjects, theABCA3sequence variants were missense variants, small insertions or deletions with in-silico tools predicting some residual ABCA3 transporter function.ConclusionThe natural history of ABCA3-related interstitial lung disease progresses during childhood and adolescence. Disease-modifying treatments are desirable to delay such disease course.

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Section: Resultsmentioning

confidence: 99%

“…The position of TMDs and NBDs of ABCA3 were referred to the prediction algorithms of Onnée et al . 40 (B). Age of survival of the mutations’ carrier (y-axis) in dependency of amino acid position (x-axis).…”

Section: Resultsmentioning

confidence: 99%

ABCA3-related interstitial lung disease beyond infancy

Seidl

Knoflach

et al. 2023

Thorax

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“…ABCA3 dysfunction has also been shown to play a role in the development of pulmonary disorders such as neonatal respiratory distress and interstitial lung disease. As part of the larger ABCA family, the protein coded is responsible for specifically playing a role in the transport regulation of phosphatidylcholine, phosphatidylglycerol, phosphatidylethanolamine, and cholesterol, and is critical for pulmonary surfactant homoeostasis through an ATP dependent pathway [17]. LILRB3 codes for one of many leukocyte immunoglobulin-like receptors, which plays a role in developing our innate immune system.…”

Section: Discussionmentioning

confidence: 99%

SNARE-ing the reason for post-cardiac surgery critical illness-related corticosteroid insufficiency

Diehl

Kibiryeva

Marshall

et al. 2023

Preprint

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Critical illness-related corticosteroid insufficiency (CIRCI) can cause hemodynamic instability in neonates after congenital heart surgery with manifestations that increase morbidity and potential mortality. We retrospectively reviewed neonates who underwent cardiac surgery between August 2018 to July 2020 at a Midwest freestanding children’s hospital. Of the 96 neonates who had cardiac surgery, for further inclusion, neonates had to have had both a cortisol level and next gene sequencing (NGS) drawn as a standard of care after cardiac surgery. Demographics and surgical outcomes were compared. Groups were defined by CIRCI with a cortisol level < 4.5 mcg/dL and non-CIRCI groups (level > 4.5 mcg/dL). DNA-Seq analysis was performed for each neonate in the DNA module of Partek FLOW software and filtered for confidence of mutations of 20 or above. Analysis excluded all common variants (detectable in more than 1% of the general population). Additionally, Bowtie2 was used to align reads to hg38 and Partek Genotype likelihood algorithm to identify a list of aberrations for each neonate. Those de-identified cohorted groups (CIRCI and non-CIRCI) were uploaded into Clinical Insight (Qiagen) for variant interpretation with biologic filters of pulmonary hypertension and hemodynamic instability. Neonates included in study analysis (n=16) demonstrated 206,409 variants which were then evaluated through biological filters. Similar types of cardiac diagnosis and surgeries were seen with trending rates of higher reintubation rate and longer lengths of stay within the CIRCI group. Seven gene mutations were found present in 75-100% of neonates with CIRCI (n=8) with 0-25% incidence of those corresponding mutations in neonates in the non-CIRCI group (n=8). CIRCI group had 100% incidence of heterozygous gene mutation on STX1A with splicing or loss of function with no findings of this mutation in the non-CIRCI group. Additional gene mutations were found in CIRCI group on RAB6A, ABCA3, SIDT2, and LILRB3 with no incidence in the non-CIRCI group. There were three additional mutations found across CIRCI 3Click here to enter text. group in INPPL1 and FAM189A2 (both splicing and missense) with 12-25% of patients in the non-CIRCI group also displaying these mutations. Novel genetic abnormalities were seen in neonates with symptoms of CIRCI with potential cardiac implications from gene mutation for STX1A. Additionally, compounding effects of the same patients having gene mutations on RAB6A, ABCA3, SIDT2, and LILRB3, INPPL1, and FAM189A2 need to be confirmed and explored for potential predisposition for hemodynamic instability during times of stress. Long-term potential aligns with the development of a genetic biomarker panel to be performed prior to neonatal cardiac surgery to identify genes predisposing neonates to the development of postoperative complications of CIRCI.

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“…Before our study, several attempts have been applied to the computational 3D structural modeling of human ABCA3 to understand the possible impact of pathogenic variants (41)(42)(43). These computational 3D models were built on the basis of the type IV ABC fold (41), the TMDs-NBDs of nucleotide-free ABCA1 structure (42), and the TMDs-NBDs-RDs of ATP-bound ABCA4 structure (43), respectively, and thus provide inaccurate and limited interpretation of ABCA3 variants. The high-resolution structures of ABCA3 in both nucleotide-free and ATP-bound states presented here could provide direct insights into the mechanistic basis for the pathogenic mutations.…”

Section: Structural Interpretation Of the Disease-associated Mutationsmentioning

confidence: 99%

Cryo-EM structures of the human surfactant lipid transporter ABCA3

et al. 2022

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The adenosine 5′-triphosphate (ATP)–binding cassette (ABC) transporter ABCA3 plays a critical role in pulmonary surfactant biogenesis. Mutations in human ABCA3 have been recognized as the most frequent causes of inherited surfactant dysfunction disorders. Despite two decades of research, in vitro biochemical and structural studies of ABCA3 are still lacking. Here, we report the cryo-EM structures of human ABCA3 in two distinct conformations, both at resolution of 3.3 Å. In the absence of ATP, ABCA3 adopts a “lateral-opening” conformation with the lateral surfaces of transmembrane domains (TMDs) exposed to the membrane and features two positively charged cavities within the TMDs as potential substrate binding sites. ATP binding induces pronounced conformational changes, resulting in the collapse of the potential substrate binding cavities. Our results help to rationalize the disease-causing mutations in human ABCA3 and suggest a conserved “lateral access and extrusion” mechanism for both lipid export and import mediated by ABCA transporters.

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Structure-Based Understanding of ABCA3 Variants

Cited by 9 publications

References 42 publications

ABCA3-related interstitial lung disease beyond infancy

ABCA3-related interstitial lung disease beyond infancy

SNARE-ing the reason for post-cardiac surgery critical illness-related corticosteroid insufficiency

Cryo-EM structures of the human surfactant lipid transporter ABCA3

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