Alternative titles; symbols
HGNC Approved Gene Symbol: SFTPA2
Cytogenetic location: 10q22.3 Genomic coordinates (GRCh38) : 10:79,555,852-79,560,407 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q22.3 | Interstitial lung disease 2 | 178500 | Autosomal dominant | 3 |
Katyal et al. (1992) isolated and characterized SFTPA2, which encodes an isoform of surfactant-associated protein SPA (SFTPA1; 178630). SFTPA1 and SFTPA2 both contain a consensus recognition sequence for initiation, TATAAA, and a polyadenylation signal sequence. Transcripts of both genes were found in adult human lung by Northern blot analysis.
Wang et al. (2009) noted that the 248-amino acid SFTPA2 protein contains a collagen-like region, a neck domain, and a C-terminal carbohydrate-recognition domain. SFTPA2 shares greater than 98% amino acid identity with SFTPA1 across the coding region and greater than 90% amino acid identity across noncoding regions.
Katyal et al. (1992) determined that the SFTPA2 gene contains 5 exons.
Kolble et al. (1993) presented evidence for a cluster of pulmonary surfactant-associated proteins on chromosome 10q22-q23. They constructed a phylogenetic tree showing the relationships of SPAI (SFTPA1), SPAII, mannose-binding lectin (MBL; 154545), SPB (178640), and SPC (178620) proteins.
Stumpf (2021) mapped the SFTPA2 gene to chromosome 10q22.3 based on an alignment of the SFTPA2 sequence (GenBank BC111571) with the genomic sequence (GRCh38).
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.
In affected members of 2 families with interstitial lung disease-2 (ILD2; 178500), some of whom also had lung cancer, Wang et al. (2009) identified 2 heterozygous missense mutations in the SFTPA2 gene (G231V, 178642.0001 and F198S, 178642.0002, respectively). Both mutations involve highly conserved residues in the carbohydrate recognition domain (CRD) and were predicted to disrupt protein structure; transfection studies in A549 human alveolar epithelial cells showed that the mutant proteins were retained in the endoplasmic reticulum and not secreted.
In 11 probands with ILD2, Legendre et al. (2020) identified heterozygous missense mutations in the SFTPA2 gene (see, e.g, 178642.0003-178642.0005). The mutations, which were found by direct sequencing, were either absent from or found at a low frequency in the gnomAD database. The mutation segregated with the disorder in families from whom DNA was available; there was evidence of incomplete penetrance and variable expressivity. In vitro functional expression studies in HEK293T cells transfected with the mutations showed normal protein expression with decreased secretion of SFTPA1 compared to controls. Abnormal cytoplasmic retention of mutant SFTPA1 in the alveolar epithelium was considered to contribute to pathogenicity.
In affected members of a 4-generation family (F27) with interstitial lung disease-2 (ILD2; 178500), some of whom also had lung cancer, Wang et al. (2009) identified heterozygosity for a c.692G-T transversion in exon 6 of the SFTPA2 gene, resulting in a gly231-to-val (G231V) substitution at a highly conserved residue in the carbohydrate recognition domain (CRD). The mutation was not found in 3,557 population-based controls. Transfection studies in A549 human alveolar epithelial cells showed that the mutant protein was retained in the endoplasmic reticulum and not secreted.
In a 45-year-old Caucasian male (CKG810) with interstitial lung disease-2 (ILD2; 178500) and lung cancer (see 211980), Wang et al. (2009) identified heterozygosity for a c.593T-C transition in exon 6 of the SFTPA2 gene, resulting in a phe198-to-ser (F198S) substitution at a highly conserved residue in the carbohydrate recognition domain (CRD). The proband reported multiple family members with pulmonary fibrosis and/or lung cancer, but they were not available for study. The patient had no personal smoking history, but smoking status of his childhood home was unclear. The mutation was not found in 3,557 population-based controls. Transfection studies in A549 human alveolar epithelial cells showed that the mutant protein was retained in the endoplasmic reticulum and not secreted.
In a patient (family 4) with interstitial lung disease-2 (ILD2; 178500), Legendre et al. (2020) identified a heterozygous c.512A-T transversion (c.512A-T, NM_001098668.2) in exon 6 of the SFTPA2 gene, resulting in an asn171-to-ile (N171I) substitution in the CRD domain. The mutation, which was found by direct sequencing, was not found in the gnomAD database. In vitro functional expression studies in HEK293T cells transfected with the mutation showed normal protein expression with decreased secretion of SFTPA1 compared to controls. Abnormal cytoplasmic retention of mutant SFTPA1 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 3 patients from 2 unrelated families (families 5 and 6) with interstitial lung disease-2 (ILD2; 178500), Legendre et al. (2020) identified a heterozygous c.532G-A transition (c.532G-A, NM_001098668.2) in exon 6 of the SFTPA2 gene, resulting in a val178-to-met (V178M) substitution in the CRD domain. The mutation, which was found by direct sequencing, was found at a low frequency in the gnomAD database (3 of 250,974 alleles). One unaffected family member in family 5 carried the mutation, consistent with incomplete penetrance. In vitro functional expression studies in HEK293T cells transfected with the mutation showed normal protein expression with decreased secretion of SFTPA1 compared to controls. Abnormal cytoplasmic retention of mutant SFTPA1 in the alveolar epithelium was considered to contribute to pathogenicity. The proband in family 6 had 2 similarly affected deceased family members, including those with lung cancer, but DNA from those individuals was not available for segregation studies.
In a mother and son (family 8) with interstitial lung disease-2 (ILD2; 178500), Legendre et al. (2020) identified a heterozygous c.697T-A transversion (c.697T-A, NM_001098668.2) in exon 6 of the SFTPA2 gene, resulting in a trp233-to-arg (W233R) substitution in the CRD domain. The mutation, which was found by direct sequencing, was not present in the gnomAD database. In vitro functional expression studies in HEK293T cells transfected with the mutation showed normal protein expression with decreased secretion of SFTPA2 compared to controls. Abnormal cytoplasmic retention of mutant SFTPA2 in the alveolar epithelium was considered to contribute to pathogenicity. There was a significant family history of similar lung disease, including lung cancer, but DNA from affected family members was not available for segregation studies.
Katyal, S. L., Singh, G., Locker, J. Characterization of a second human pulmonary surfactant-associated protein SP-A gene. Am. J. Resp. Cell Molec. Biol. 6: 446-452, 1992. [PubMed: 1372511] [Full Text: https://doi.org/10.1165/ajrcmb/6.4.446]
Kolble, K., Lu, J., Mole, S. E., Kaluz, S., Reid, K. B. M. Assignment of the human pulmonary surfactant protein D gene (SFTP4) to 10q22-q23 close to the surfactant protein A gene cluster. Genomics 17: 294-298, 1993. [PubMed: 8406480] [Full Text: https://doi.org/10.1006/geno.1993.1324]
Legendre, M., Butt, A., Borie, R., Debray, MP., Bouvry, D., Filhol-Blin, E., Desroziers, T., Nau, V., Copin, B., Dastot-Le Moal, F., Hery, M., Duquesnoy, P., and 29 others. Functional assessment and phenotypic heterogeneity of SFTPA1 and SFTPA2 mutations in interstitial lung diseases and lung cancer. Europ. Resp. J. 56: 2002806, 2020. [PubMed: 32855221] [Full Text: https://doi.org/10.1183/13993003.02806-2020]
Ramet, M., Lofgren, J., Albo, O.-P., Hallman, M. Surfactant protein-A gene locus associated with recurrent otitis media. J. Pediat. 138: 266-268, 2001. [PubMed: 11174628] [Full Text: https://doi.org/10.1067/mpd.2001.110133]
Stumpf, A. M. Personal Communication. Baltimore, Md. 11/16/2021.
Wang, Y., Kuan, P. J., Xing, C., Cronkhite, J. T., Torres, F., Rosenblatt, R. L., DiMaio, J. M., Kinch, L. N., Grishin, N. V., Garcia, C. K. Genetic defects in surfactant protein A2 are associated with pulmonary fibrosis and lung cancer. Am. J. Hum. Genet. 84: 52-59, 2009. [PubMed: 19100526] [Full Text: https://doi.org/10.1016/j.ajhg.2008.11.010]