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					Familial Pulmonary Disorders
      Christine Garcia, MD, PhD
             July 28, 2006
The Respiratory System


        Nasal
        cavity


                 mouth
               Pulmonary Disease
           Abnormal     Normal        Abnormal
           Scarring                  Destruction
                         Lung
Fibrosis
  (IPF)                                    Emphysema




    Surfactant C gene            Alpha-1-antitrypsin
 Idiopathic Pulmonary Fibrosis

Clinical features:

     Age of onset: 60’s
     Incidence: 15 per 100,000
     Males > females
     Smoking predisposition
     Mean age to death: 3 - 5 years
     No definitive treatments
       Is There a Fibrosis Gene?

• Familial clustering of pulmonary fibrosis
• Observed in genetic disorders with diverse
  presentations
• Development in “susceptible” individuals
  following an environmental exposure
• Different susceptibility of inbred mice to
  radiation and/or bleomycin
  Familial Pulmonary Fibrosis in the UK

• Familial cases account for 0.5 – 2.2 % of
  cases
• Prevalence of 1.34 : 1,000,000
• HRCT for 93% cases, OLBx for 32%
• No attempt to sub-classify IIP by pathology
• Younger age, male predominant, 50%
  smokers, 36% exposed to known
  fibrogenic agents, consistent with
  autosomal dominant inheritance
                         Thorax 2000 55: 143-146
  Familial Pulmonary Fibrosis in the US

• Three sites in the United States (Denver,
  Vanderbilt, and Duke) found 111 families
• All subjects submitted blood samples and
  underwent CXR PA/Lat and DLco.
• Any subjects with dyspnea, abnormality, or
  self-reported ILD, underwent HRCT.
• Subjects with HRCT suggestive of an IIP
  were recommended to obtain an OLBx.

                         AJRCCM (2005) 172: 1146-1152
    Features Associated with FIP
• Older age
• Male sex
• Smoking history
• Autosomal dominant inheritance in
    20 pedigrees
• 45% with phenotypic heterogeneity
• Range of 2 - 7 cases per family
       Is There a Fibrosis Gene?

• Familial clustering of pulmonary fibrosis
• Observed in genetic disorders with diverse
  presentations
• Development in “susceptible” individuals
  following an environmental exposure
• Different susceptibility of inbred mice to
  radiation and/or bleomycin
Genetic Mutations associated with
    Pediatric Lung Diseases

   • Surfactant Protein B
   • ATP-binding cassette transporter A3



   • Surfactant Protein C
Surfactant Protein C Mutation Associated
 with Familial Interstitial Lung Disease



Lung disease
            1 year



          DIP
        6 weeks



   NSIP


                        NEJM (2001) 344: 573-579
Surfactant Protein C Associated with
    UIP and NSIP in one Family




                       AJRCCM 165:1322-28(2002)
       Is There a Fibrosis Gene?

• Familial clustering of pulmonary fibrosis
• Observed in genetic disorders with diverse
  presentations
• Development in “susceptible” individuals
  following an environmental exposure
• Different susceptibility of inbred mice to
  radiation and/or bleomycin
     Susceptibility to Asbestosis

• CXR survey of shipyard workers have
  shown that 32 -- 44% have parenchymal
  radiographic abnormalities.
• 3.3% had extensive pulmonary fibrosis.
       Is There a Fibrosis Gene?

• Familial clustering of pulmonary fibrosis
• Observed in genetic disorders with diverse
  presentations
• Development in “susceptible” individuals
  following an environmental exposure
• Different susceptibility of inbred mice to
  radiation and/or bleomycin
Approach to Study Familial
  Pulmonary Disorders
   • PHENOTYPE!
   • Evaluate Candidate Loci
   • Genome-wide analysis
   • PHENOTYPE AGAIN!
             Our Approach

• Recruitment of patients with IPF
• Completion of a questionnaire, donation of
  a blood sample, obtain medical records
• Family expansion
• Phenotype individuals at risk based upon
  their position in the family
Collection of Familial Pulmonary Fibrosis
     Family   Dx of IPF   Possible PF   Total
      #27        5            5          10
      #11        5            4          9
      #29        1            5          6
      #1         0            5          5
      #15        0            4          4
      #8         2            1          3
      #21        2            1          3
      #3         2            1          3
      #31        2            1          3
      #7         1            2          3
      #2         1            2          3
      #4         0            3          3
                    Familial Pulmonary Fibrosis
                                                              64     67


                                                     CAD CHF

               72                         85        72                                       38   82
                                                                              6
                                               Lung                                 Pulmonary
     CAD                                      disease                                fibrosis
          37                     52      78              49        54         73 76     51    47       54
                    2
Pulmonary                Lung CA                              IPF        Lung CA      IPF Pulmonary
 fibrosis
                                                                                           fibrosis
         41                     50                  41    10             52
                            2        2                                            2

    IPF                 Pulmonary             IPF                  IPF
                         fibrosis
                                                                                        Family #27
Approach to Study Familial
  Pulmonary Disorders
   • PHENOTYPE!
   • Evaluate Candidate Loci
   • Genome-wide analysis
   • PHENOTYPE AGAIN!
               Pulmonary Disease
                         Normal
                          Lung
         Scarring                       Destruction
Fibrosis                                    Emphysema




Idiopathic pulmonary fibrosis   Spontaneous pneumothorax
The Secondary Pulmonary Lobule




                  Distal acinar emphysema:
                  Results in blebs/bullae
                  Associated with spontaneous PTX
Isolated Spontaneous Pneumothorax
 Clinical features:
      Age of onset: 20’s to 30’s
      Males > females
      Asthenic build
      Smoking predisposition
      10% have positive family history

 Associated with genetic disorders:
      Marfans syndrome – FBN1 (fibrillin)
      Alpha-1-antitrypsin deficiency – SERPINA1
      Ehlers-Danlos syndrome
      Birt-Hogg-Dubé syndrome - FLCN
             Skin lesions – onset in 30’s
             Renal cancer – onset in 50’s
Birt-Hogg-Dubé Syndrome




              Fibrofolliculomas
Isolated Spontaneous Pneumothorax
     • Collected 23 families
     • Segregation of candidate genes
     • 8 families co-segregated with FLCN
     Familial Spontaneous Pneumothorax

I.
                           1       2


II.
           1       2       3   4           5        6


III.
       1       2       3   4   5          6             7
                                       Pneumothorax (PTX)

                                       Unaffected
Photographs taken at Surgery of Ind. III:1
A                    B
Pathologic sections from Resected Lung




    Individual II:2   Individual III:5
Gene Loci Ruled Out by Haplotype Analysis

      •   Fibrillin-1   •   COL1A1
      •   TGFBR2        •   COL1A2
      •   SERPINA1      •   TNXB
                        •   PLOD
      •   COL3A1        •   ADAMTS2
      •   COL5A2        •   ATP7A
      •   COL5A1        •   FN1
FLCN
FLCN Locus Not Ruled Out by Haplotype Analysis
Mutations in Folliculin Found in Isolated
 Familial Spontaneous Pneumothorax
             Summary of Mutations of FLCN
Familial
spontaneous                                c.853C>T
                                                                            c.1252delC

pneumothorax                                                                c.1285_1286insC

             c.499_509delCAGCGCTGGTA                   c.890_893delAAAG

             c.584delG                                 c. 943G>T                     c.1429C>T

  c.33C>A                              IVS7-2AC                                        c.1592_1593delAC
  c.235_238delTCGG

 Exon           4        5       6        7        8       9       10     11       12        13     14
    c.58delT                 c.584delG                             c.1285_1286insC
                                                                                        c.1490_1491ins
                    c.252delC                                      c.1285delC           CTGT
 IVS4-1GA                           c.632_633delAGinsC                                           c.1579CT
                    c.296delA                                  IVS9+1GA
                                     c.637delT
                                                               IVS9+2TG        c.1303delT
                                     c.671_672delCA
Birt-Hogg-                                                     IVS9+2TG        c.1379_1380delTC
Dubé                                                                            c.1389CG
                                                 c.923_950dup
syndrome                                                                        c.1426_1427insG
                                                 c.1013delG
Am.J.Genet. 76:1023-1033, 2005                                                  c.1429CT
                                                 c.1018delC
            Folliculin

• Mutations in gene cause BHD
  syndrome and isolated
  familial spontaneous pneumothorax.
• Unknown function.
             Folliculin



•   579 amino acids; 65kD
•   No significant homology to other proteins
•   Cytoplasmic localization
•   Expressed in multiple tissues
•   Loss of heterozygosity in renal cancers
                 Genome +              β-geo
  Strategy for Knock-out
Generation of flcn Knock Out Mice
                      Random
                                  vector integration


                    5       6           β-geo              7


                                   Spliced transcript
                                   Prematurely-terminated protein
                                   β-galactosidase


                           FLCN       β-geo
             Acknowledgements

     The Lab:                   McDermott Center:
•   Phillip Kuan                • Robert Barnes, MS
•   Kalliopi Tsakiri            • Alison Cook
•   Jennifer Cronkhite, PhD     • Holly Brookman
•   Melissa Nolasco


                 Collaborators:
                • Pulmonary faculty
                  for their referrals

				
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