Genetics in pulmonary fibrosis--familial cases provide clues to the pathogenesis of idiopathic pulmonary fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is the most common form of the idiopathic interstitial pneumonias and remains a disease with a poor prognosis. Familial interstitial pneumonia (FIP) occurs when 2 or more individuals from a given family have an idiopathic interstitial pneumonia. FIP cases have been linked to mutations in surfactant protein C, surfactant protein A2, telomerase reverse transcriptase and telomerase RNA component. Together, mutations in these 4 genes likely explain only 15% to 20% of FIP cases and are even less frequent in sporadic IPF. However, dysfunctional aspects of the pathways that are involved with these genes are present in sporadic forms of IPF even in the absence of mutations, suggesting common underlying disease mechanisms. By serving as a resource for identifying the current and future genetic links to disease, FIP families hold great promise in defining IPF pathogenesis, potentially suggesting targets for the development of future therapies.

Figure 1

Pedigree of a family with familial interstitial pneumonia (FIP), condensed from a larger pedigree in the Vanderbilt FIP Registry. This pedigree represents a four generation pedigree in which individuals from two generations (II and III) had documented cases of pulmonary fibrosis (PF). Two individuals in generation III had documented usual interstitial pneumonia (UIP) on surgical lung biopsy. Individuals in the fourth generation remain asymptomatic to date with no documented case of pulmonary fibrosis. This pedigree demonstrates an autosomal dominant pattern of inheritance with a single parent passing an aberrant gene on to children, including male to male transmission. While the genetic mutation responsible for pulmonary fibrosis is not known in this family, two individuals (denoted with gray) are obligate carriers for the gene in question (female in generation I, and second male in generation II). Squares denote males; circles denote females. Black filling denotes individuals affected with pulmonary fibrosis; gray filling denotes individuals that are obligate carriers for the dysfunctional gene in this family; empty squares and circles denote unaffected individuals. Strikethrough symbol (/) denotes individuals who are no longer living. Bx = biopsy.