Alternative titles; symbols
HGNC Approved Gene Symbol: SFTPB
Cytogenetic location: 2p11.2 Genomic coordinates (GRCh38): 2:85,657,307-85,668,741 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2p11.2 | Surfactant metabolism dysfunction, pulmonary, 1 | 265120 | Autosomal recessive | 3 |
The SFTPB gene encodes the pulmonary-associated surfactant B protein (SPB), an amphipathic surfactant protein essential for lung function and homeostasis after birth. Pulmonary surfactant is a lipid-rich material that prevents lung collapse by lowering surface tension at the air-liquid interface in the alveoli of lung. SPB enhances the rate of spreading and increases the stability of surfactant monolayers in vitro. Surfactant is composed of phospholipids and other surfactant-associated proteins (Clark et al., 1995). See also SFTPA1 (178630), SFTPC (178620), and SFTPD (178635).
Glasser et al. (1987) isolated cDNA clones corresponding to the SFTPB gene from a human lung cDNA library. Northern blot analysis detected 2.0- and 1.7-kb transcripts. Mature SPB is a 79-residue protein with a molecular mass of 8.7 kD. The mature form is produced by extensive proteolytic processing of a 381-residue precursor protein (proSPB) in type II alveolar cells. Active SPB is a disulfide-linked homodimer (Johansson et al., 1992; Whitsett and Weaver, 2002). The active SPB peptide is processed and packaged into lamellar bodies before secretion with phospholipids into the alveolar airspace (Voorhout et al., 1992).
Phelps and Floros (1991) found that SFTPB expression is limited to type II alveolar cells and club cells, which line the primary bronchioles of the lung.
Pilot-Matias et al. (1989) determined that the SFTBP gene contains 11 exons and spans approximately 9.5 kb. The gene contains a large 823-nucleotide 3-prime untranslated exon.
The precursor SPB protein is specified by exons 1 to 10, whereas the mature SPB protein is encoded by exons 6 and 7 (Tredano et al., 1999).
By human-CHO somatic cell hybridization, Emrie et al. (1988) mapped the SFTPB gene to chromosome 2. Pilot-Matias et al. (1989) also mapped this gene to chromosome 2 by Southern analysis of mouse-human hybrid cell DNA. Vamvakopoulos et al. (1995) mapped the SFTP3 gene to 2p12-p11.2 by fluorescence in situ hybridization.
The corresponding gene in the mouse (Sftp3) maps to chromosome 6 (Moore et al., 1992).
Pulmonary Surfactant Metabolism Dysfunction 1
In 3 sibs with neonatal pulmonary surfactant metabolism dysfunction (SMDP1; 265120) due to surfactant protein B deficiency, Nogee et al. (1994) identified a homozygous mutation in the SFTPB gene (178640.0001). The authors referred to this mutation as '121ins2.'
In an infant with fatal neonatal respiratory distress and pulmonary alveolar proteinosis due to surfactant B deficiency, Wallot et al. (1999) identified a homozygous mutation in the SFTPB gene (178640.0002). The patient was born to consanguineous Kurdish parents and had 4 similarly affected relatives.
In a review of hereditary surfactant protein B deficiency, Whitsett and Weaver (2002) stated that more than 22 distinct mutations in the SFTPB gene that cause respiratory failure had been identified (Nogee et al., 2000). The 121ins2 mutation accounted for approximately two-thirds of mutant SFTPB alleles.
Possible Association With Respiratory Distress Syndrome of Prematurity
Among 684 premature neonates, of whom 184 developed respiratory distress syndrome associated with prematurity (RDS; 267450), Haataja et al. (2000) found an association with an ile131-to-thr (I131T) polymorphism in the SFTPB gene and specific polymorphic alleles in the SFTPA1 gene, suggesting an interaction between the 2 genes. Among the infants born before 32 weeks' gestation and having the SFTPB genotype 131thr/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).
Rova et al. (2004) found an association between an SPB intron 4 deletion polymorphism and bronchopulmonary dysplasia in 365 preterm Finnish infants (gestational age 32 weeks). The frequency of the intron 4 deletion variant allele was increased in patients versus controls (P = 0.008) and was a risk factor for the disease even when essential external confounding factors were included in the analyses. Allele-specific differences were predicted at several putative transcription factor binding sites that may be important in SPB regulation. The authors proposed that 2 separate SPB gene polymorphisms may have a phenotypic significance via separate molecular mechanisms: the intron 4 length variation affecting transcriptional regulation, and the exonic ile131-to-thr variation affecting posttranslational regulation.
Hamvas et al. (1995) reported an infant with SPB deficiency and compound heterozygosity for the 121ins2 mutation who lived longer than infants homozygous for the mutation and seemed to respond to glucocorticoid administration.
Clark et al. (1995) demonstrated that Spb-null mice died of respiratory failure immediately after birth. Lungs of Spb-null mice developed normally, but remained atelectatic in spite of postnatal respiratory efforts. In lung tissue, Spb protein and mRNA were undetectable. Fully formed lamellar bodies and tubular myelin, the intracellular and extracellular forms of surfactant, respectively, were lacking, suggesting a disruption of routing, storage, and function of surfactant. An aberrant form of proSPC was detected. Heterozygous mice showed no abnormalities.
Tokieda et al. (1999) found that Spb -/+ mice had abnormal pressure-volume relations during pulmonary function testing and were susceptible to oxygen-induced lung injury. The findings suggested that Spb may play a protective role in the lung.
In 3 sibs with fatal neonatal respiratory insufficiency due to surfactant metabolism dysfunction and surfactant protein B deficiency (SMDP1; 265120), Nogee et al. (1994) identified a homozygous 2-bp insertion in exon 4 of the SFTPB gene. The mutation consisted of a 375C-GAA change, resulting in a frameshift and premature termination of the protein. Three other unrelated patients also carried the mutation. Nogee et al. (1994) referred to the mutation as '121ins2.' The mutation was not identified in 100 control chromosomes.
Tredano et al. (1999) referred to this mutation as g.1549C-GAA.
Clark and Clark (2005) estimated a gene frequency of 1 in 1,000 individuals for the 121ins2 mutation.
By haplotype analysis of the SFTPB gene in 17 independent 121ins2-carrying chromosomes from 10 probands and 21 parental noncarrier control chromosomes, Tredano et al. (2006) found evidence for a common ancestor from a region of northwestern Europe populated by Frankish/Saxon migration, accounting for the majority of, if not all, extant 121ins2 chromosomes.
In an infant from a consanguineous Kurdish kindred with neonatal surfactant metabolism dysfunction due to surfactant protein B deficiency (SMDP1; 265120), Wallot et al. (1999) identified a homozygous 1-bp deletion (1553delT) in exon 4 of the SFTPB gene, resulting in a premature termination codon at amino acid 214 in exon 6. No mature protein was produced. Four relatives had a similar phenotype. All were full-term infants who presented in the neonatal period and 4 died at 2 to 7 weeks despite intensive care; 1 survived until age 8 months, but eventually died.
In a full-term infant with severe neonatal respiratory insufficiency (SMDP1; 265120), Tredano et al. (1999) identified compound heterozygosity for 2 mutations in the SFTPB gene: a 1-bp deletion (457delC) inherited from the mother and the common 121ins2 mutation (178640.0001) inherited from the father. Analysis of bronchoalveolar lavage fluid demonstrated complete absence of SPB. However, unlike previous infants with hereditary SPB deficiency, proSPC was processed to the active SPC peptide. The infant survived 27 days; no postmortem examination was performed.
In a full-term infant with respiratory insufficiency (SMDP1; 265120), Ballard et al. (1995) identified compound heterozygosity for 2 mutations in the SFTPB gene: the common 121ins2 mutation (178640.0001) and a C-to-T transition in exon 7, resulting in an arg236-to-cys (R236C) substitution. Each unaffected parent was heterozygous for 1 of the mutations. The infant required extracorporeal bypass for 2 weeks and was ventilator- and oxygen-dependent until his unexpected death at age 9.5 months. Postmortem investigation showed low but detectable levels of SPB and near-normal SPB mRNA, suggesting a partial deficiency.
In 2 unrelated patients of French Canadian descent with pulmonary surfactant metabolism dysfunction-1 (SMDP1; 265120), Dunbar et al. (2000) identified a homozygous 479G-T (g.2479) transversion in codon 155 of exon 5 of the SFTPB gene. The substitution was not predicted to result in an amino acid sequence change, but it created an alternative donor splice site resulting in the deletion of 119 bases from exon 5 and a premature termination of the protein in exon 7. Analysis of mRNA detected 3 different SPB species: a normal sequence, a pathogenic truncated species resulting from the newly created splice site, and a transcript that lacked exon 7 and would not allow translation of the exons that encode mature SPB. Western blot analysis detected reduced amounts of mature SPB as well as an aberrant SPB product that corresponded to translation of an abnormal transcript lacking exon 7; this latter species was also found in controls. The phenotype of both patients was less severe than that reported in other patients with SPB deficiency. The first child underwent bilateral lung transplant at age 4 months and the second child survived to age 6 years with persistent oxygen requirement. The older child developed pulmonary hypertension and right ventricular hypertrophy. Immunohistochemical analysis showed residual SPB protein in both cases, although it was higher in the older child. Dunbar et al. (2000) concluded that the decreased severity of lung disease in these patients may be related to the production of low levels of normal SPB or partial function of an aberrant proSPB protein. The findings indicated that there is variability in phenotypic expression of surfactant B deficiency.
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