Original Article
A common mutation in the surfactant protein C gene associated with lung disease

https://doi.org/10.1016/j.jpeds.2004.10.028Get rights and content

Objective

To determine the contribution of the surfactant protein C (SP-C) I73T mutation to lung disease.

Study design

Genomic DNA was obtained from 116 children with interstitial lung disease (ILD) or chronic lung disease of unclear cause and from 166 control subjects and was screened for the I73T mutation using an allele-specific polymerase chain reaction assay.

Results

The I73T mutation was found on 7 of 232 SP-C alleles from 7 unrelated children with ILD but was not found on 332 control SP-C alleles (P < .01, Fisher exact test). The I73T mutation segregated with lung disease in one kindred with familial ILD. The I73T mutation was found in an asymptomatic parent from two different families with affected children consistent with variable penetrance, but it was not found in either asymptomatic parent of two other unrelated affected children consistent with a de novo mutation. Analysis of single nucleotide polymorphisms indicated diverse genetic backgrounds of the I73T alleles. Immunohistochemical analysis of lung tissue from an infant with the I73T mutation demonstrated normal staining patterns for proSP-B, SP-B, and proSP-C.

Conclusions

These findings support the hypothesis that the I73T mutation predisposes to or causes lung disease.

Section snippets

Patients and DNA

Patient samples were obtained as part of a collaborative study involving the Johns Hopkins Children's Center Hospital, St Louis Children's Hospital, and Cincinnati Children's Hospital to evaluate infants with lung disease of unknown cause for mutations in the surfactant protein genes. Samples were also recruited from physicians from other medical centers familiar with our work who were interested in having their patients evaluated for potential SP-B and SP-C gene abnormalities. The

Results

The I73T mutation was first identified by DNA sequence analysis of the SP-C gene in a 33-week-gestation female infant who initially presented with symptoms consistent with RDS but failed to wean off supplemental oxygen by 2 years of age. Evaluation was prompted when her mother was diagnosed with restrictive pneumonitis after delivery, and additional family history revealed an extensive familial lung disease kindred (Figure 1). A heterozygous thymine-to-cytosine transition was identified at

Discussion

We have identified a novel SP-C gene mutation, I73T, in multiple unrelated infants with lung disease. Although adult family members with the mutation who do not currently have lung disease were identified, incomplete penetrance has been recognized with another SP-C gene mutation with onset of lung disease in some individuals as late as the 6th decade.8 The segregation of the mutation with disease in the one extended kindred, the absence of the mutation in healthy control subjects, and the de

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  • Cited by (0)

    Supported in part by grants from the National Institutes of Health [HL-54703 (L.M.N), HL-56387 (J.A.W., S.E.W., L.M.N.), HL-65174 (A.H.)], Forest Pharmaceuticals (H.S.C.), and the Eudowood Foundation.

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