Published ahead of print on April 1, 2005, doi:10.1164/rccm.200501-143OC Am. J. Respir. Crit. Care Med., Volume 172, Number 1, July 2005, 39-44 A more recent version of this article appeared on July 1, 2005
Submitted on January 28, 2005 Nonsense Mutations in Folliculin Presenting as Isolated Familial Spontaneous Pneumothorax in AdultsRandall B Graham1,1 Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Texas Southwestern Medical Center, Eugene McDermott Center for Human Growth and Development, Dallas, TX, USA, 2 Division of Medical Genetics, University Medical Center Ljublijana, Ljublijana, Slovenia * To whom correspondence should be addressed. E-mail: christine.garcia{at}utsouthwestern.edu.
Rationale: Approximately ten percent of patients who have a spontaneous pneumothorax have a positive family history. Objectives: We sought to identify DNA sequence variations that confer susceptibility to pneumothoraces. Methods: We collected twelve families which had at least two first degree relatives with a spontaneous pneumothorax. All affected family members had no obvious stigmata of known genetic disorders associated with pneumothoraces. We used haplotype analysis, DNA sequencing, and restriction fragment analysis of mutations to evaluate the individuals in these families. Main Results: In two of the twelve families the disorder cosegregated with markers flanking a candidate locus, FLCN. Sequencing the linked alleles revealed two mutations predicted to introduce premature stop codons in two of the twelve families. Most mutations in FLCN cause a rare disease, Birt-Hogg-Dube syndrome, characterized by autosomal dominant inheritance of multiple benign skin lesions, renal tumors, pulmonary blebs, and pneumothoraces. None of the family members with the nonsense mutations had the skin manifestations of Birt-Hogg-Dube syndrome or renal cancer. Pathologic examination of lung tissue from three affected nonsmokers revealed blebs and underlying emphysema. Conclusions: Thus, isolated familial spontaneous pneumothorax can be caused by mutations of the FLCN gene. Since development of a pneumothorax and/or pulmonary blebs may be the earliest or the only clinical manifestation of FLCN mutations, pulmonologists should be alert to the contribution of this gene toward this familial form of emphysema. Key words: familial pneumothorax, human BHD protein, pulmonary emphysema, genetics
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