Familial Pulmonary Disorders Christine Garcia, MD, PhD July 28, 2006

1. Thank you Dr. ____ for inviting me to speak here today. I wanted to give a broad overview of ongoing projects in the lab and then focus on one familial pulmonary disorder for we have made some progress. The lungs are the human body’s bellows and gas exchange system all in one. Just like other organ systems, genetics has an important impact on many aspects of lung structure and function – from the shape of the thoracic cage, to neurologic control of breathing, to the intrinsic response of the lung parenchyma to various insults. Being a geneticist, I’ve taken the approach of searching for rare human families with disease that can be followed within the family with the ultimate goal of determining the genes responsible for disease. Thank you Dr. ____ for inviting me to speak here today. I wanted to give a broad overview of ongoing projects in the lab and then focus on one familial pulmonary disorder for we have made some progress. The lungs are the human body’s bellows and gas exchange system all in one. Just like other organ systems, genetics has an important impact on many aspects of lung structure and function – from the shape of the thoracic cage, to neurologic control of breathing, to the intrinsic response of the lung parenchyma to various insults. Being a geneticist, I’ve taken the approach of searching for rare human families with disease that can be followed within the family with the ultimate goal of determining the genes responsible for disease.

2. Every day each one of you breaths 15,000L of air. This air has to travel across the nasal/oral mucosa, the pharynx, trachea, throughout the tracheobronchial tree, where it reaches a huge alveolar surface. This surface measures in excess of 150 sq m, like the surface of a tennis court. There are genetic factors that impact the different facets of this system. For example, genes that influence patterns of breathing, the nature of the mucous coating the trancheobronchial tree (CFTR), response to infection, response to inflammation/proteases (A1AT). Every day each one of you breaths 15,000L of air. This air has to travel across the nasal/oral mucosa, the pharynx, trachea, throughout the tracheobronchial tree, where it reaches a huge alveolar surface. This surface measures in excess of 150 sq m, like the surface of a tennis court. There are genetic factors that impact the different facets of this system. For example, genes that influence patterns of breathing, the nature of the mucous coating the trancheobronchial tree (CFTR), response to infection, response to inflammation/proteases (A1AT).

3. Prototypical disease is IPF, idiopathic pulmonary fibrosis. Incidence of 13 – 20 / 100,000. Terrible, progressive disease, with ave. survival of 2-3 years after diagnosis with few treatments available except oxygen and lung transplantation. Many clinical trials for antifibrotic agents in progress. Familial cases account for 0.5 – 2.2%. Clinical features of familial cases identical to the sporadic form, except that the familial form has an earlier age of onset. UK study showed that the average age of onset was 55 for the familial form, but 68 years for the sporadic form. AD with incomplete penetrance. Prototypical disease is IPF, idiopathic pulmonary fibrosis. Incidence of 13 – 20 / 100,000. Terrible, progressive disease, with ave. survival of 2-3 years after diagnosis with few treatments available except oxygen and lung transplantation. Many clinical trials for antifibrotic agents in progress. Familial cases account for 0.5 – 2.2%. Clinical features of familial cases identical to the sporadic form, except that the familial form has an earlier age of onset. UK study showed that the average age of onset was 55 for the familial form, but 68 years for the sporadic form. AD with incomplete penetrance.

10. Other genes associated with pediatric lung disease/respiratory distress of the newborn: Surfactant protein B deficiency, ABCA3. Usually die within 1 month of birth, OLBx show various expression of PAP, DIP, abnormal lamellar bodies in the type II alveolar cells. SFTPB assoc with PAP, pulmonary fibrosis. ABCA3 assoc with PAP, DIP, chronic pneumonitis of infancy There are different pulmonary pathologies associated with mutation of one gene. One example where there is great diversity of phenotypic manifestations (pleiotrophy) is SFTPC. This gene has relevance to pediatric pulmonologists and adult pulmonologists. Other genes associated with pediatric lung disease/respiratory distress of the newborn: Surfactant protein B deficiency, ABCA3. Usually die within 1 month of birth, OLBx show various expression of PAP, DIP, abnormal lamellar bodies in the type II alveolar cells. SFTPB assoc with PAP, pulmonary fibrosis. ABCA3 assoc with PAP, DIP, chronic pneumonitis of infancy There are different pulmonary pathologies associated with mutation of one gene. One example where there is great diversity of phenotypic manifestations (pleiotrophy) is SFTPC. This gene has relevance to pediatric pulmonologists and adult pulmonologists.

11. Full term baby girl born to woman with dx of DIP. Rx’d with steroids until age 15. Maternal grandfather died from life-long lung disease of unknown cause. At six weeks of age, baby developed respiratory symptoms of tachypnea and cyanosis on RA. OLBx with cellular or NSIP. Rx with O2 and steroids. Mother worsened after delivery and died. Full term baby girl born to woman with dx of DIP. Rx’d with steroids until age 15. Maternal grandfather died from life-long lung disease of unknown cause. At six weeks of age, baby developed respiratory symptoms of tachypnea and cyanosis on RA. OLBx with cellular or NSIP. Rx with O2 and steroids. Mother worsened after delivery and died.

12. SPCTC locus 8p21 Mutations associated with a larger spectrum of lung pathology: “fibrocystic pulmonary dysplasia”, “interstitial pulmonary fibrosis (Hamman-Rich)”, NSIP, UIP In general, presentation is at a young age. This family presentation from 4 mo to 57 yo mean age of 27yo. Mutation is a heterozygous T ? A change that changes a well conserved Leu at position 188 to Gln. EM shows abnormal lamellar bodies in the type II cells. Transfection of the mutant construct into mouse lung epithelial cell line led to increased cytotoxicity. SPCTC locus 8p21 Mutations associated with a larger spectrum of lung pathology: “fibrocystic pulmonary dysplasia”, “interstitial pulmonary fibrosis (Hamman-Rich)”, NSIP, UIP In general, presentation is at a young age. This family presentation from 4 mo to 57 yo mean age of 27yo. Mutation is a heterozygous T ? A change that changes a well conserved Leu at position 188 to Gln. EM shows abnormal lamellar bodies in the type II cells. Transfection of the mutant construct into mouse lung epithelial cell line led to increased cytotoxicity.

14. Extensive pulmonary fibrosis was defined as parenchymal changes involving over ½ of the lung fields. It would be expected that if all the parenchymal changes were due to asbestos exposure, there would be a higher percentage of abnormalities with advancing age or increasing time since the onset of asbestos exposure. This was not the case. May due to other environmental factors (cigarette smoking or exposure to other toxic agents) or genetic factors, or both. Extensive pulmonary fibrosis was defined as parenchymal changes involving over ½ of the lung fields. It would be expected that if all the parenchymal changes were due to asbestos exposure, there would be a higher percentage of abnormalities with advancing age or increasing time since the onset of asbestos exposure. This was not the case. May due to other environmental factors (cigarette smoking or exposure to other toxic agents) or genetic factors, or both.

26. Proband was tall, no Marfan features, no joint hyperextensibility No skin phenotype of BHD – seen regularly by dermatologist because of resected melanoma in his 20s Had 4 PTX, beginning at the age of 24. Aunt with 1 PTX at 29, another aunt with 1 PTX at 59, One cousin with 2 PTX at 23, male cousin with 4 PTX beginning at age 30. Proband was tall, no Marfan features, no joint hyperextensibility No skin phenotype of BHD – seen regularly by dermatologist because of resected melanoma in his 20s Had 4 PTX, beginning at the age of 24. Aunt with 1 PTX at 29, another aunt with 1 PTX at 59, One cousin with 2 PTX at 23, male cousin with 4 PTX beginning at age 30.

33. Continue to collect families with FSP, and we have found mutations in FLCN in 8 of 23 families. We have also found the mutation 3 individuals with sporadic pneumothorax. This slide summarizes the mutations … mutation found in Painter et al… Subgroup of families with FSP actually represent a forme fruste of BHD. Two important points: All patients sent to us did not have a dx of BHD. PTX is the first or dominant manifestation All mutations are loss of function mutations which span the coding region of the gene. Folliculin has an important role in these two diseases. What does it do? Continue to collect families with FSP, and we have found mutations in FLCN in 8 of 23 families. We have also found the mutation 3 individuals with sporadic pneumothorax. This slide summarizes the mutations … mutation found in Painter et al… Subgroup of families with FSP actually represent a forme fruste of BHD. Two important points: All patients sent to us did not have a dx of BHD. PTX is the first or dominant manifestation All mutations are loss of function mutations which span the coding region of the gene. Folliculin has an important role in these two diseases. What does it do?