Genetic Variability of Surfactant Protein-B and Respiratory Distress Syndrome: Clinical Implications

, Departments of Cellular and Molecular Physiology and Pediatrics; , Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pa.

In This Article

Pulmonary Surfactant Protein B (SP-B)

Physiological Importance

The importance of SP-B in respiratory function has been documented by a variety of studies: a) When a monoclonal antibody to SP-B was instilled through the trachea of near-term newborn rabbits, the animals developed respiratory failure;[19] b) When the SP-B monoclonal antibody was mixed with a surfactant preparation used in surfactant replacement of surfactant-deficient rabbits born prematurely at 26 days of gestation (term = 31 days), the biological activity of surfactant was decreased;[20] c) When modified surfactant preparations prepared from extracts of minced cow lungs were supplemented with SP-B and then used in surfactant treatment of prematurely-born rabbits, their functional activity was improved;[21] d) Infants with fatal congenital alveolar proteinosis are deficient in SP-B;[16,22] and e) Homozygous SP-B "deficient" mice (SP-B expression is genetically eliminated) do not survive.[23] We conclude from these findings that SP-B is essential for respiratory function. Furthermore, the evidence suggests that suboptimal amounts of SP-B, comparable to that found in heterozygous SP-B-deficient mice, although compatible with life, may present certain small abnormalities in function, such as decreased compliance and increased air-trapping.[24] We do not know if the impact of these abnormalities increases in the setting of certain pulmonary diseases.

Mutations and Polymorphisms of SP-B

A number of mutations and polymorphisms have been identified within the SP-B gene. As indicated earlier, examples of different types of mutations/polymorphisms are depicted in Figure 2. Documented mutations/polymorphisms within the SP-B gene are depicted in Figure 3. The known mutations (shown in red), 1549ins2[25] and 1553delT,[26] lead to a lack of mature SP-B. Some of the polymorphisms (because of their location within the SP-B gene) have the potential to affect the regulation and/or splicing efficiency of SP-B.

For example, the C/A substitution at nucleotide position -18 (the nucleotide which starts the transcription -- the process that turns DNA into RNA -- of a gene is numerically assigned a position of +1; all sequences located upstream from this start point, ie, 5' flanking sequences, are designated to occupy a "minus" position relative to start), is 10 nucleotides downstream of the TATA box (the transcription initiation signal), and the G/A at nucleotide position 9306 is four nucleotides upstream of the TAATAAA polyadenylation signal (signals the site where a poly-A tail, a run of consecutive adenine nucleotides, is added to the 3' end of mammalian pre-mRNAs); whereas the G/A, at nucleotide 1013 is within the consensus splicing sequence of the intron II/exon III junction. The two mutations, 1549ins2 and 1553delT, and one polymorphism, C/T at 1580, are located within a short 32-nucleotide region in exon IV. Because of the high frequency of mutations/polymorphisms, a detailed analysis of the exon IV region was conducted. The findings showed that this region has the characteristics of a "hot spot" for mutations.[26] The term "hot spot" is used to indicate that some genes may be in regions of chromosomes which are more susceptible to genetic damage/change or may contain sequences that are more likely to be altered by spontaneous mutations. The role, if any, of the other polymorphisms shown in Figure 3 is currently unknown. The polymorphic region containing the composite (CA)n repeat in intron IV, described above, is found in higher frequency in RDS and is discussed below in "Genetics and RDS."

The known SP-B mutations/polymorphisms within the coding region of SP-B and the corresponding amino acid changes are shown in Figure 4. The mutations (shown in red) lead to lack of mature SP-B and thus to SP-B deficiency.[16,25] The missense mutations, with the exception of the G/A substitution at 4376, result in a change of the encoded amino acid. Of these, Gly151Ser causes a transient SP-B deficiency,[26] and Arg236Cys is associated with a partial SP-B deficiency[17] (both are shown in green). The missense mutation Thr131Ile (shown in purple) is located within a potential N-linked glycosylation motif of SP-B protein. The change from Thr to Ile eliminates the potential glycosylation site. We do not know if this potential site is glycosylated in vivo or what the consequences are if this site is lost.[7]

Mutations in human SP-B coding region.


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