Nonsense Mutations in Folliculin Presenting as Isolated Familial Spontaneous Pneumothorax in Adults

• Published in: American journal of respiratory and critical care medicine 2005-07, Vol.172 (1), p.39-44
• Main Authors: Graham, Randall B, Nolasco, Melissa, Peterlin, Borut, Garcia, Christine Kim
• Format: Article
• Language: English
• Subjects: Adult; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Biological and medical sciences; Blood and lymphatic vessels; Cancer; Cardiology. Vascular system; Codon, Nonsense; Connective tissue diseases; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Emphysema; Estrone - genetics; Family medical history; Female; Genes, Dominant; Haplotypes; Humans; Intensive care medicine; Longitudinal Studies; Male; Marfan syndrome; Medical sciences; Middle Aged; Mutation; Neurology; Pedigree; Pneumothorax; Pneumothorax - genetics; Polymorphism, Restriction Fragment Length; Proteins; Proteins - genetics; Proto-Oncogene Proteins; Pulmonary Emphysema - genetics; Sequence Analysis, RNA; Skin; Surveys and Questionnaires; Tumor Suppressor Proteins; Tumors; Vascular diseases and vascular malformations of the nervous system
• ISSN: 1073-449X; 1535-4970
• DOI: 10.1164/rccm.200501-143OC

Approximately 10% of patients who have a spontaneous pneumothorax have a positive family history. We sought to identify DNA sequence variations that confer susceptibility to pneumothoraces. We collected 12 families that had at least 2 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. In 2 of the 12 families the disorder cosegregated with markers flanking a candidate locus, FLCN. Sequencing the linked alleles revealed 2 mutations predicted to introduce premature stop codons in 2 of the 12 families. Most mutations in FLCN cause a rare disease, Birt-Hogg-Dubé 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-Dubé syndrome or renal cancer. Pathologic examination of lung tissue from three affected nonsmokers revealed blebs and underlying emphysema. Isolated familial spontaneous pneumothorax can be caused by mutations of the FLCN gene. Because 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.