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Genetic mutations in surfactant protein C are a rare cause of sporadic cases of IPF
Lawson WE, et al. Thorax. 2004;59:977-980.

Introduction:

Idiopathic Pulmonary Fibrosis (IPF) is a devastating disease characterized by the inexorable accumulation of extracellular matrix in the interstices of the lung leading to respiratory failure and death in the majority of patients within 5 years of diagnosis. Of patients with IPF, 2-20% have a family history of pulmonary fibrosis. It is often difficult to ascertain the presence of pulmonary fibrosis in families because of the late age of onset in most patients and poor diagnostic tests. Inheritance appears to be dominant with variable penetrance. Interestingly, not all family forms of pulmonary fibrosis have the pathologic features of usual interstitial pneumonia (UIP), but may have nonspecific interstitial pneumonia or fibrosing cryptogenic pneumonia. Loyd and colleagues (Lawson et al) identified a large kindred with a mutation in the gene encoding surfactant protein C in affected family members, but it does not appear that this mutation accounts for the majority of familiar cases. Armanios et al had the insight to investigate the potential relationship between dyskeratosis congenita and familial pulmonary fibrosis. Dyskeratosis congenita:

Is a rare hereditary disorder
Presents with mucocutaneous manifestations and bone marrow failure
Includes pulmonary fibrosis in 20% of affected individuals with both X-linked and autosomal dominant forms
Is a disorder in which heterozygous mutations in telomerase underlie the genetic defect in families with dominant inheritance

Telomerase is a specialized polymerase that adds telomere repeats to the ends of chromosomes. Telomere shortening occurs during DNA replication; when shortening reaches a threshold, a DNA damage response results leading to cell death by apoptosis. Telomerase has two essential components: a catalytic component, telomerase reverse transcriptase (hTERT); and an RNA component (hTR). Armanios et al identified a pedigree with autosomal dominant dyskeratosis congenita that carried a null hTERT allele but lacked the typical mucocutaneous features. In this kindred, pulmonary fibrosis was dominantly transmitted. This finding led to a collaboration between Armanios and colleagues at Johns Hopkins with Loyd and colleagues at Vanderbilt, who have collected samples from families with IPF.

Findings:

73 probands were screened and 6 (8%) had heterozygous mutations in hTERT or hTR. The pattern of inheritance was consistent with autosomal dominant inheritance of the disease.

Mutation carriers who did not have symptoms of the disease were identified and were, on average, 11 years younger than the probands at the time of diagnosis.
Mutations associated with disease were also associated with short lymphocyte telomeres and impaired telomerase activity.
None of the probands had features of dyskeratosis congenita.
The probands had typical presentations of IPF and 5 of the 6 that underwent surgical biopsy demonstrated UIP.
This study shows that mutant telomerase is associated with familial IPF.
Short dysfunctional telomeres can lead to cell death and this would be expected to manifest in cells that have a rapid turnover such as bone marrow and skin epithelium.
These findings might suggest that alveolar epithelium has a rapid turnover like GI or skin epithelium, but this has not been demonstrated.
It is not clear how these telomerase mutations would lead to selective lung fibrosis.
It is interesting that both cigarette smoking and aging can lead to telomerase shortening and both of these are risk factors for IPF.

A second study by Tsakiri et al used a different approach but also identified mutations in telomerase in familial IPF.
- Linkage was used to map the disease gene in 2 families to chromosome 5.
- A candidate gene approach was based on the association of hTERT with dyskeratosis congenita.
- Sequencing the probands of 44 additional unrelated families and 44 sporadic cases of IPF revealed 5 other mutations in hTERT.
- These results further suggest that telomerase shortening could be a significant event in the development of IPF.

Expert Opinion:

These results are exciting and even though mutations in the essential components of telomerase do not seem to account for the vast majority of cases of familial IPF, this clue could lead to new insights into pathogenesis and treatment for IPF. Furthermore, these results support emerging concepts that IPF is a result of dysfunctional communication between alveolar epithelium and mesenchyme leading to a pro-fibrotic environment. Caution is suggested in pursuing genetic testing until more information becomes available on telomerase mutations.

References

Article Links

Lawson WE, et al. Genetic mutations in surfactant protein C are a rare cause of sporadic cases of IPF. Thorax. 2004;59:977-980.
Click here for a direct link to the article abstract.

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