Alternative titles; symbols
HGNC Approved Gene Symbol: SFTPA1
Cytogenetic location: 10q22.3 Genomic coordinates (GRCh38): 10:79,610,939-79,615,455 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q22.3 | Interstitial lung disease 1 | 619611 | Autosomal dominant; Autosomal recessive | 3 |
Pulmonary surfactant is a phospholipid-protein complex that serves to lower the surface tension at the air-liquid interface in the alveoli of the lung. It is essential to normal respiration. Inadequate amounts of surfactant at birth, a frequent situation in premature infants, results in respiratory failure. Pulmonary surfactant is composed primarily of dipalmitoylphosphatidylcholine and 2 major protein species of relative molecular weights 32,000 and 10,000. Latt (1987) indicated that the smaller apoprotein has a molecular weight of 6,000 rather than 10,000. White et al. (1985) cloned the PSAP gene. They pointed to a TATAAA sequence about 100 bp upstream from the first exon, which is a potential binding site for glucocorticoid. Extensive evidence indicates that glucocorticoids regulate surfactant synthesis. The protein has Gly-X-Y triplets like collagen, acetylcholinesterase, and C1q of complement, suggesting an evolutionary relationship. They found that the amino acid sequence of glycoprotein in alveolar proteinosis corresponded precisely to that predicted by the PSAP gene. Glasser et al. (1987) presented data on the cDNA sequence and the deduced amino acid sequence of human pulmonary surfactant-associated proteolipid, called by them SPL(Phe) because of the N-terminal phenylalanine.
Gardai et al. (2003) found that the collectins SPA and SPD (SFTPD; 178635) helped maintain a noninflammatory environment in lung by stimulating the immunoreceptor tyrosine-based inhibitory motif (ITIM)-containing SIRPA (PTPNS1; 602461) on resident alveolar cells through their globular head, C-lectin domains. However, when these domains interacted with pathogen-associated molecular patterns (PAMP) on foreign organisms, apoptotic cells, or cell debris, presentation of the collectins' collagenous tails in an aggregated state to CALR (109091)/CD91 (LRP1; 107770) on the alveolar cells initiated ingestion and generation of proinflammatory and proimmunogenic responses. Gardai et al. (2003) proposed that SPA and SPD act as dual-function surveillance molecules that reverse orientation and function and become initiators of host-defense reactions.
The SFTPA1 gene contains 4 coding exons (Ramet et al., 2000).
By Southern blot analysis of hybrid cell DNA and by in situ hybridization, Bruns et al. (1987) showed that each of 2 closely related cDNA clones for the major 35-kD pulmonary surfactant-associated proteins was coded by 10q21-q24. The isolation of 2 nonidentical cDNAs for PSP-A and their in vitro translation into 2 proteins of slightly different apparent molecular weights may indicate allelic variation at the PSP-A locus or a family of closely related genes located at 10q21-q24. Using a mapping panel of somatic cell hybrids, Fisher et al. (1987) likewise assigned PSAP to chromosome 10. They also identified 2 MspI RFLPs in the coding sequence of PSAP. The corresponding gene in the mouse, Sftp-1, maps to chromosome 14; Sftp-2 maps to a different location on the same chromosome (Moore et al., 1992).
The human SPA gene locus consists of 2 highly homologous functional genes, SFTPA1 and SFTPA2 (178642), and a pseudogene located on 10q (Ramet et al., 2000).
Stumpf (2021) mapped the SFTPA1 gene to chromosome 10q22.3 based on an alignment of the SFTPA1 sequence (GenBank BC111570) with the genomic sequence (GRCh38).
Kolble et al. (1993) constructed a phylogenetic tree for the SFTP genes and mannose-binding lectin (MBL; 154545). MBL, SFTP1, and SFTP4 all show domains of collagen-like Gly-X-Y triplets.
Possible Association With Respiratory Distress Syndrome Associated with Prematurity
Several alleles that differ by a single amino acid had been identified in each SFTPA gene (Floros et al., 1996). The alleles of the SFTPA1 gene are denoted as '6A(n),' and those of the SFTPA2 gene as '1A(n)' (Floros and Hoover, 1998). In Finland, Ramet et al. (2000) found that certain SFTPA1 alleles, 6A(2) and 6A(3), and a SFTPA1/SFTPA2 haplotype, 6A(2)/1A(0), were associated with respiratory distress syndrome (RDS; 267450). The 6A(2) allele was overrepresented and the 6A(3) allele was underrepresented in infants with RDS. These associations were particularly strong among small premature infants born at gestational age less than 32 weeks.
Haataja et al. (2000) genotyped 684 prematurely born neonates (of whom 184 developed RDS) at polymorphic sites in the SFTPA1 and SFTPB (178640) proteins. Two SFTPB polymorphisms were used: the ile131-to-thr variation affects a putative N-terminal, N-linked glycosylation site of proSFTPB, and the length variation of intron 4 has previously been suggested to associate with RDS. Neither of the SFTPB polymorphisms associated directly with RDS or with prematurity. Rather, the previously identified association between SFTPA1 alleles and RDS was dependent on the SFTPB ile131-to-thr genotype. On the basis of chi square and logistic regression analyses, the SFTPA1 allele, haplotype, and genotype distributions differed significantly between the RDS infants and controls only when the SFTPB genotype was thr/thr. Among the infants born before 32 weeks' gestation and having the SFTPB genotype thr/thr, the SFTPA1 allele 6A2 was overrepresented in the RDS group compared with controls. In the same comparison, the SFTPA1 allele 6A3 was underrepresented in RDS. The authors proposed that the SFTPB ile131-to-thr polymorphism is a determinant for certain SFTPA1 alleles as factors causing genetic susceptibility to RDS (6A2, 1A0) or protection against it (6A3, 1A2).
Interstitial Lung Disease 1
Selman et al. (2003) examined associations between idiopathic pulmonary fibrosis, a form of interstitial lung disease (see ILD1, 619611) and genetic polymorphisms of surfactant proteins SPA1 (SFTPA1), SPA2 (SFTPA2), SPB (SFTPB), SPC (SFTPC; 178620), and SPD (SFTPD; 178635). One SPA1 allele, designated 6A(4), carried a missense variant (R219W; 178630.0001), present in other SPA1 alleles and in all SPA2 alleles. To explore whether the trp219 protein altered protein behavior, Selman et al. (2003) oxidized 2 truncated proteins that varied only at amino acid 219 by exposure to ozone. Differences in the absorption spectra between the 2 truncated recombinant SPA proteins were observed both before and after protein oxidation, suggesting allele-specific aggregation differences attributable to amino acid 219. The trp219 allele was found in higher frequency in nonsmokers with idiopathic pulmonary fibrosis.
In 6 members of a large multigenerational French family with interstitial lung disease-1 (ILD1; 619611), Nathan et al. (2016) identified a heterozygous missense mutation in exon 6 of the SFTAP1 gene (W211R; 178630.0003). The mutation occurred at a conserved residue in the carbohydrate recognition domain (CRD). The mutation, which was found by direct sequencing, was not present in the dbSNP, 1000 Genomes Project, or ExAC databases. The variant segregated with the disorder, although there were 3 asymptomatic carriers, indicating incomplete penetrance. Analysis of HEK293 cells transfected with the mutant protein showed that it was expressed at normal levels, but that secretion was absent. Immunohistochemical studies of lung tissue from 1 affected patient with ILD showed an abnormal cellular expression pattern of SFTAP1.
In 4 affected members of a 3-generation Czech family with ILD1, Doubkova et al. (2019) identified a heterozygous missense mutation in the CRD domain of the SFTAP1 gene (V178M; 178630.0004). The mutation, which was found by a combination of whole-exome sequencing and candidate gene sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed.
In 2 unrelated probands with ILD1, Legendre et al. (2020) identified heterozygous missense mutations at conserved residues in the CRD domain (V178M, 178630.0004 and V255M, 178630.0005). In vitro functional expression studies in HEK293T cells of both V178M and V255M showed normal protein expression with decreased secretion of SFTAP1 compared to controls. Abnormal cytoplasmic retention of mutant SFTAP1 in the alveolar epithelium was considered to contribute to pathogenicity. Both patients had a family history of similar lung disease, but DNA was not available for segregation studies.
In 3 brothers, born of consanguineous Japanese parents, with autosomal recessive ILD1, Takezaki et al. (2019) identified a homozygous missense mutation at a conserved residue in the CRD domain (Y208H; 178630.0006). The mutation, which was found by a combination of homozygosity mapping and exome sequencing and confirmed by Sanger sequencing, was not present in the 1000 Genomes Project or ExAC databases. Each parent was heterozygous for the mutation and clinically unaffected, although lung imaging was not performed on them. These findings were consistent with autosomal recessive inheritance. In vitro cellular expression studies showed that the mutation impaired secretion of SFTPA1.
Other Disease Associations
Surfactant protein A, which plays a role in innate host defense in the lung, is also expressed in the eustachian tube. Ramet et al. (2001) reported that the frequency of specific surfactant protein A haplotypes and genotypes differs between children with recurrent otitis media compared with a control population in Finland.
Malik et al. (2006) reported a significant association (p = 0.007 after Bonferroni correction) between a synonymous 307G-A SNP in the SFTPA1 gene, resulting in a P62P substitution, and susceptibility to tuberculosis (607948) in an Ethiopian population. The authors suggested that the polymorphism may affect splicing and/or mRNA maturation. Malik et al. (2006) noted that Floros et al. (2000) had previously reported an association between SFTPA1 polymorphisms and tuberculosis in a Mexican population.
Ketko et al. (2013) found that Spa -/- mice infected intratracheally with wildtype flagellated Pseudomonas aeruginosa (PA) showed increased recruitment of inflammatory cells and increased production of Il6 (147620) and Tnf (191160). These responses were not observed in Spa -/- mice infected with mutant PA lacking flagella. Human SPA, via N-linked carbohydrate moieties and a collage-like domain, directly bound flagellin in a concentration-dependent manner. Examination of Spa -/- and wildtype mouse macrophages showed that Spa enhanced macrophage phagocytosis of flagellin and wildtype PA. Il1b (147720) was reduced in lungs of Spa -/- mice following PA infection. Stimulation of a mouse macrophage cell line with flagellin and SPA enhanced Il1b production in a Casp1 (147678)-dependent manner. Ketko et al. (2013) concluded that SPA plays an important role in the pathogenesis of PA infection in lung by binding flagellin, enhancing its phagocytosis, and modifying the macrophage inflammatory response.
Using immunohistochemistry, Bhatti et al. (2015) found that Spa was present in mouse retina at birth and colocalized with a marker of Muller cells. Stimulation with Tlr2 (603028) and Tlr4 (603030) ligands resulted in increased Spa expression in wildtype mouse retina, but not Myd88 (602170) -/- mouse retina, in which the NFKB (see 164011) pathway is inactive. SPA expression was also increased in a human Muller cell line following stimulation with TLR2 and TLR4 ligands. Retinal Spa was increased in wildtype mice subjected to oxygen-induced retinopathy (OIR) compared with controls, and Spa -/- mice had reduced neovascularization in response to OIR compared with wildtype mice. Bhatti et al. (2015) concluded that retinal and Muller cell SPA is upregulated via the NFKB pathway and during the hypoxia phase of OIR. They proposed that SPA may be a marker of retinal inflammation during neovascularization.
Takezaki et al. (2019) found that knockin mice with a homozygous Y208H (178630.0006) mutation in the Sftpa1 gene developed progressive pulmonary fibrosis associated with collagen deposition in the lung. Infection with the influenza virus accelerated the fibrosis in mutant mice. Bronchoalveolar lavage fluid from mutant mice did not contain Sftpa1, consistent with impaired secretion of the protein. Detailed studies of the mice indicated that type II alveolar epithelial cells underwent necroptosis, which is a type of cell death that stimulates an immune response. There was evidence of increased ER stress as well as activation of JNK (see 601158) and Ripk3 (605817), which forms a complex that activates caspase (see 600636) to cause cell death. The authors concluded that the pathogenesis of pulmonary fibrosis may be due to a necroptosis signaling pathway.
This variant, formerly titled PULMONARY FIBROSIS, IDIOPATHIC, SUSCEPTIBILITY TO, has been reclassified because it represents a polymorphism and its contribution to idiopathic pulmonary fibrosis, a form of interstitial lung disease (ILD1; 619611), has not been confirmed.
Selman et al. (2003) studied 84 unrelated patients with idiopathic pulmonary fibrosis. Among 54 nonsmokers, they found a significant association between idiopathic pulmonary fibrosis and a heterozygous C-to-G transversion in the SFTPA1 gene, designated 6A(4), resulting in an arg219-to-trp (R219W) substitution. The variant allele was found in 7.8% of controls and 22.2% of patients, yielding an odds ratio (OR) of 3.13 (p = 0.02). Functional studies of a truncated protein carrying an arg or trp at residue 219 showed that trp219 resulted in increased absorption at 310 to 350 nm wavelength after oxidation compared to arg219, suggesting that the variant caused an alteration in self-aggregation properties. Selman et al. (2003) speculated that polymorphisms in surfactant genes may result in subtle changes in protein structure and/or function that may contribute to increased susceptibility to pulmonary disease.
This variant is classified as a variant of unknown significance because it represents a polymorphism and its contribution to idiopathic pulmonary fibrosis, a form of interstitial lung disease (ILD1; 619611), has not been confirmed.
In 7 of 10 Chinese patients with idiopathic pulmonary fibrosis, Zhang et al. (2012) identified a homozygous C-to-A transversion in exon 6 of the SFTPA1 gene, resulting in a gln238-to-lys (Q238K) substitution. Three patients were heterozygous for the variant. Heterozygosity for the variant was found in 8 of 30 control patients with pneumonia and in 11 of 30 healthy volunteers. None of the controls was homozygous for the variant. The difference in allele frequency between patients and controls was significant. Functional studies of the variant were not performed, but protein homology modeling suggested that the variant could change the 3D structure of the protein.
In 6 members of a large multigenerational French family with interstitial lung disease-1 (ILD1; 619611), Nathan et al. (2016) identified a heterozygous c.631T-C transition (c.631T-C, NM_005411.4) in exon 6 of the SFTAP1 gene, resulting in a trp211-to-arg (W211R) substitution at a conserved residue in the CRD domain. The mutation, which was found by direct sequencing, was not present in the dbSNP, 1000 Genomes Project, or ExAC databases. Two of the clinically affected mutation carriers developed lung adenocarcinoma, indicating variable expressivity. The variant segregated with the disorder, although there were 3 asymptomatic carriers, indicating incomplete penetrance. Analysis of HEK293 cells transfected with the mutation showed that it was expressed at normal levels, but that secretion was absent. Immunohistochemical studies of lung tissue from 1 affected patient with ILD showed an abnormal cellular expression pattern of SFTAP1 with discontinuous and mostly intracytoplasmic staining of hyperplastic pneumocytes, which contrasted with a continuous linear layer of SFTPA1 at the alveolar surface in controls.
Legendre et al. (2020) reported this family (family 2, PP005) as part of a larger series of patients with ILD, noting that the W211R mutation is not present in the gnomAD database. In vitro functional expression studies in HEK293T cells confirmed normal protein expression with decreased secretion of SFTAP1 compared to controls. Abnormal cytoplasmic retention of mutant SFTAP1 in the alveolar epithelium was considered to contribute to pathogenicity.
In 4 affected members of a 3-generation Czech family with interstitial lung disease-1 (ILD1; 619611), Doubkova et al. (2019) identified a heterozygous c.532G-A transition (NM_005411.4) in exon 6 of the SFTAP1 gene, resulting in a val178-to-met (V178M) substitution at a highly conserved residue in the CRD domain. The mutation, which was found by a combination of whole-exome sequencing and candidate gene sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. A fifth asymptomatic family member also carried the mutation, indicating incomplete penetrance. The mutation was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed.
In a 68-year-old man of North African descent (family 1, GM01220) with ILD1, Legendre et al. (2020) identified a heterozygous V178M mutation. The mutation, which was found by direct sequencing, was found once in the gnomAD database (1 of 250,994 alleles). In vitro functional expression studies in HEK293T cells showed normal protein expression with decreased secretion of SFTAP1 compared to controls. Abnormal cytoplasmic retention of mutant SFTAP1 in the alveolar epithelium was considered to contribute to pathogenicity. The patient had a significant family history of similar lung disease, but DNA from affected family members was not available for segregation studies.
In a woman (family 3, GM0537) with interstitial lung disease-1 (ILD1; 619611), Legendre et al. (2020) identified a heterozygous c.673G-A transition (c.673G-A, NM_005411.5) in exon 6 of the SFTAP1 gene, resulting in a val225-to-met (V255M) substitution at a conserved residue in the CRD domain. The mutation, which was found by direct sequencing, was not present in the gnomAD database. The patient's clinically unaffected daughter carried the mutation, consistent with incomplete penetrance. In vitro functional expression studies in HEK293T cells showed normal protein expression with decreased secretion of SFTAP1 compared to controls. Abnormal cytoplasmic retention of mutant SFTAP1 in the alveolar epithelium was considered to contribute to pathogenicity. The patient had a significant family history of similar lung disease, but DNA from deceased affected family members was not available for segregation studies.
In 3 brothers, born of consanguineous Japanese parents, with interstitial lung disease-1 (ILD1; 619611), Takezaki et al. (2019) identified a homozygous c.622T-C transition (c.622T-C, GRCh37) in exon 6 of the SFTAP1 gene, resulting in a tyr208-to-his (Y208H) substitution at a conserved residue in the CRD domain. The mutation, which was found by a combination of homozygosity mapping and exome sequencing and confirmed by Sanger sequencing, was not present in the 1000 Genomes Project or ExAC databases. Each parent was heterozygous for the mutation and clinically unaffected, although lung imaging was not performed on them. These findings were consistent with autosomal recessive inheritance. In vitro cellular expression studies showed that the mutation impaired secretion of SFTPA1. Moreover, knockin mice with a homozygous Y208H mutation developed progressive pulmonary fibrosis associated with collagen deposition in the lung. Bronchoalveolar lavage fluid from mutant mice did not contain Sftpa1, consistent with impaired secretion of the protein.
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