Abstract
Genetic disorders of the surfactant system are rare diseases with a broad range of clinical manifestations, from fatal respiratory distress syndrome (RDS) in neonates to chronic interstitial lung disease (ILD) in children and adults. ABCA3 [ATP-binding cassette (ABC), subfamily A, member 3] is a lung-specific phospholipid transporter critical for intracellular surfactant synthesis and storage in lamellar bodies (LBs). Its expression is developmentally regulated, peaking prior to birth under the influence of steroids and transcription factors. Bi-allelicmutations of the ABCA3 gene represent the most frequent cause of congenital surfactant deficiency, indicating its critical role in lung function. Mutations affect surfactant lipid and protein processing and LBs' morphology, leading to partial or total surfactant deficiency. Approximately 200 mutations have been reported, most of which are unique to individuals and families, which makes diagnosis and prognosis challenging. Various types of mutations, affecting different domains of the protein, account in part for phenotype diversity. Disease-causing mutations have been reported in most coding and some non-coding regions of the gene, but tend to cluster in the first extracellular loop and the second nucleotide-binding domain (NBD), leading to defective glycosylation and trafficking defects and interfering with ATP binding and hydrolysis respectively. Mono-allelic damaging and benign variants are often subclinical but may act as diseasemodifiers in lung diseases such as RDS of prematurity or associate withmutations in other surfactantrelated genes. Diagnosis is complex but essential and should combine pathology and ultrastructure studies on lung biopsy with broad-spectrum genetic testing of surfactant-related genes, made possible by recent technology advances in the massive parallel sequencing technology.
| Original language | English |
|---|---|
| Pages (from-to) | 913-919 |
| Number of pages | 7 |
| Journal | Biochemical Society Transactions |
| Volume | 43 |
| DOIs | |
| Publication status | Published - Oct 1 2015 |
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Keywords
- Genetics
- Interstitial lung disease
- Neonate
- Respiratory distress syndrome
- Surfactant
- Ultrastructure
ASJC Scopus subject areas
- Biochemistry
Cite this
ABCA3, a key player in neonatal respiratory transition and genetic disorders of the surfactant system. / Peca, Donatella; Cutrera, Renato; Masotti, Andrea; Boldrini, Renata; Danhaive, Olivier.
In: Biochemical Society Transactions, Vol. 43, 01.10.2015, p. 913-919.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - ABCA3, a key player in neonatal respiratory transition and genetic disorders of the surfactant system
AU - Peca, Donatella
AU - Cutrera, Renato
AU - Masotti, Andrea
AU - Boldrini, Renata
AU - Danhaive, Olivier
PY - 2015/10/1
Y1 - 2015/10/1
N2 - Genetic disorders of the surfactant system are rare diseases with a broad range of clinical manifestations, from fatal respiratory distress syndrome (RDS) in neonates to chronic interstitial lung disease (ILD) in children and adults. ABCA3 [ATP-binding cassette (ABC), subfamily A, member 3] is a lung-specific phospholipid transporter critical for intracellular surfactant synthesis and storage in lamellar bodies (LBs). Its expression is developmentally regulated, peaking prior to birth under the influence of steroids and transcription factors. Bi-allelicmutations of the ABCA3 gene represent the most frequent cause of congenital surfactant deficiency, indicating its critical role in lung function. Mutations affect surfactant lipid and protein processing and LBs' morphology, leading to partial or total surfactant deficiency. Approximately 200 mutations have been reported, most of which are unique to individuals and families, which makes diagnosis and prognosis challenging. Various types of mutations, affecting different domains of the protein, account in part for phenotype diversity. Disease-causing mutations have been reported in most coding and some non-coding regions of the gene, but tend to cluster in the first extracellular loop and the second nucleotide-binding domain (NBD), leading to defective glycosylation and trafficking defects and interfering with ATP binding and hydrolysis respectively. Mono-allelic damaging and benign variants are often subclinical but may act as diseasemodifiers in lung diseases such as RDS of prematurity or associate withmutations in other surfactantrelated genes. Diagnosis is complex but essential and should combine pathology and ultrastructure studies on lung biopsy with broad-spectrum genetic testing of surfactant-related genes, made possible by recent technology advances in the massive parallel sequencing technology.
AB - Genetic disorders of the surfactant system are rare diseases with a broad range of clinical manifestations, from fatal respiratory distress syndrome (RDS) in neonates to chronic interstitial lung disease (ILD) in children and adults. ABCA3 [ATP-binding cassette (ABC), subfamily A, member 3] is a lung-specific phospholipid transporter critical for intracellular surfactant synthesis and storage in lamellar bodies (LBs). Its expression is developmentally regulated, peaking prior to birth under the influence of steroids and transcription factors. Bi-allelicmutations of the ABCA3 gene represent the most frequent cause of congenital surfactant deficiency, indicating its critical role in lung function. Mutations affect surfactant lipid and protein processing and LBs' morphology, leading to partial or total surfactant deficiency. Approximately 200 mutations have been reported, most of which are unique to individuals and families, which makes diagnosis and prognosis challenging. Various types of mutations, affecting different domains of the protein, account in part for phenotype diversity. Disease-causing mutations have been reported in most coding and some non-coding regions of the gene, but tend to cluster in the first extracellular loop and the second nucleotide-binding domain (NBD), leading to defective glycosylation and trafficking defects and interfering with ATP binding and hydrolysis respectively. Mono-allelic damaging and benign variants are often subclinical but may act as diseasemodifiers in lung diseases such as RDS of prematurity or associate withmutations in other surfactantrelated genes. Diagnosis is complex but essential and should combine pathology and ultrastructure studies on lung biopsy with broad-spectrum genetic testing of surfactant-related genes, made possible by recent technology advances in the massive parallel sequencing technology.
KW - Genetics
KW - Interstitial lung disease
KW - Neonate
KW - Respiratory distress syndrome
KW - Surfactant
KW - Ultrastructure
UR - http://www.scopus.com/inward/record.url?scp=84947283829&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84947283829&partnerID=8YFLogxK
U2 - 10.1042/BST20150100
DO - 10.1042/BST20150100
M3 - Article
C2 - 26517903
AN - SCOPUS:84947283829
VL - 43
SP - 913
EP - 919
JO - Biochemical Society Transactions
JF - Biochemical Society Transactions
SN - 0300-5127
ER -