Genetics of Lung Disease

©2013 Children's Mercy. All Rights Reserved. 09/13
Joshua E. Petrikin, MD
Assistant Professor of Pediatrics
Genetics of Neonatal
Respiratory Disease

2
Disclosures
 No financial disclosures
 No off-label use of products

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Objectives
 Discuss the epidemiology of RDS and BPD
 Understand the physiology of RDS
 List components and function of surfactant
 Identify candidate genes for susceptibility
of RDS
 Discuss the limitations of current studies

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Overview
 Respiratory distress syndrome (RDS)
 Surfactant overview
 Genes affecting surfactant function
 Transient tachypnea of the newborn
 Cystic fibrosis
 Primary ciliary dyskinesia

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Lung Embryology
1. Alveolar duct
2. Primary septum
3. Alveolar sac
4. Type I pneumocyte
5. Type II pneumocyte
6. Capillaries
Source: Human Embryology (Organogenesis)

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Lung Embryology, cont’d.
1. Alveolar duct
2. Secondary septum
3. Alveoli
4. Type I pneumocyte
5. Type II pneumocyte
6. Capillaries
Source: Human Embryology (Organogenesis)

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Respiratory Distress Syndrome
 Hyaline Membrane Disease
 Most common respiratory disorder in
preterm infants
 Tachypnea, retractions, grunting, nasal
flaring and hypoxia
 X-ray findings
 Volume loss, hazy “ground glass”
appearance, air-bronchograms

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RDS- CXR
Source: Respiratory Distress in the Newborn
Am Fam Physician. 2007; 76::987-994.

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Epidemiology of RDS
 40,000 affected infants each year
 20% of neonatal deaths
 Typically <35 wks GA
 Greatest risk factor: Prematurity
 500 - 750 g 86%
 751 - 1,000 g 79%
 1,001 - 1,250 g 48%
 1,251 - 1,500 g 27%

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Risk Factors for RDS
Increased Risk
Prematurity
Male gender
Familial predisposition
Cesarean section without labor
Perinatal asphyxia
Caucasian race
Infant of diabetic mother
Chorioamnionitis
Non-Immune hydrops fetalis
Decreased Risk
Chronic intra-uterine stress
Maternal hypertension or toxemia
IUGR/SGA
Antenatal glucocorticoids
Maternal use of narcotics/cocaine
Tocolytic agents
Hemolytic disease of the newborn

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Causes of RDS
 Inadequate pulmonary surfactant
 Structurally immature lung
 Decreased alveolar radius
 Weak chest wall
 Decreased compliance
 Tendency to atelectasis

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Manifestations of RDS
 Atelectasis with V/Q mismatch
 Hypoxemia and hypercardia
 Decreased 02 delivery
 Anaerobic metabolism and lactic acidosis
 Pulmonary vasoconstriction with R to L shunting
 Baro/volu/atelectotrauma and high fI02 initiate
cytokine release
 Inflammatory response with secondary endothelial
and epithelial injury

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Manifestations of RDS cont’d.
 Reduced surfactant synthesis
 Increased endothelial permeability
 Pulmonary edema
 Leakage of proteins in the alveoli further
inactivate surfactant

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Source: UCSF Medical Center

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RDS and BPD
 Risk of BPD increases with the
severity of RDS
 Risk factors for RDS likely to
affect BPD
 Logical, but unproven

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RDS Treatment
 Antenatal Steroids
 Accelerate fetal lung maturity
by increasing surfactant
formation and release
 Exogenous surfactant

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RDS Candidate Genes
 Genes affecting the surfactant system
 Genes affecting postnatal adaptation
 Genes regulating inflammatory
responses and development

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Biosynthesis of pulmonary surfactant synthesis of the protein and
phospholipid components of surfactant may proceed via separate
pathways (green lines).
Perez-Gil J , and Weaver T E Physiology 2010;25:132-141
©2010 by American Physiological Society

Participation of proteins SP-B and SP-C in surfactant dynamics during respiratory
compression-expansion cycling Hydrophobic surfactant proteins play key roles in
facilitating optimal dynamic behavior of surfactant during breathing.

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Surfactant Apoproteins
 SP-A
 Hydrophilic
 Most abundant
 Role in structure, metabolism and
function of surfactant
 Role in host defense – innate immunity

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 SP-B
 Hydrophobic
 Direct affect on biophysical properties of
surfactant lipids
 Vital for surfactant function

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 SP-C
 Hydrophobic
 Direct affect on biophysical properties of
surfactant lipids
 Vital for surfactant function

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 SP-D
 Structurally homologous to SP-A
 Role in host defense – innate immunity
 Soluble opsonin in the alveolar lining
layer

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Surfactant Protein A
 Low levels in respiratory secretions – More severe RDS
 Subsequent BPD
 Binds to microbes and promotes phagocytosis
 Enhances surfactant activity
 Protects against inactivation serum
 SP-A knockout mice have normal surfactant function
 Minor changes in metabolism
 Proposed redundancy in the system
 Accelerates phospholipid film formation with SP-B
 Most evident at low phospholipid concentrations – like premature
lung

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SP-A and RDS
 SP-A may trigger partition
 Polymorphism could lead to prematurity
 Two genes for SP-A
 Produce two separate helices that oligomerize
 Main SP-A1 allele – 6A2 – protective against RDS
 SP-A 6A2 allele combined with SP-B Thr131
polymorphism increased risk of RDS
 In the smallest babies, but not near term

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SP-A and CLD
 SP-A knockout mice susceptible to large number of
pathogens
 GBS, Pseudomonas, Staph, and RSV
 Promote surfactant function and serves as innate
immunity
 Might be differently regulated
 Infection and inflammation affect severity of RDS and
development of CLD
 Suspected etiology of SP-A polymorphisms leading to
RDS and CLD

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Surfactant Proteins B and C
 Hydrophobic Proteins directly affecting biophysical properties of
surfactant
 Enhance rate of phospholipid surface film at the air-liquid interface
 Increase lung compliance
 Preserve the integrity of distal airways
 Low levels associated with RDS
 Presence of variant alleles associated with RDS, but not any
particular variants
 Except for the threonine allele SP-B 131Thr with SP-A 6A2
 Mechanism unclear-does not affect production, processing nor folding
 Deficiency of either leads to severe lung disease

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SP-B Deficiency
 Mutations leading to deficiency cause lethal respiratory disease
 Essential to surfactant structure and to intracellular processing
 Essential for processing and secretion of SP-C
 Knockout mice lack SP-C as well
 Phenotype is term infant with severe RDS
 Can be milder if up to 5-10% of SP-B present
 Rare syndrome 1 in 1.5 million births
 66% are a 121ins2 frameshift mutation
 Responsive to surfactant therapy
 True deficiency fatal without lung transplant
 New lung has correct genes

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SP-C and RDS
 Among most hydrophobic natural polypeptides
known
 Pre-protein of 197 AA
 Processing of pre-protein linked to SP-B
 Animal studies suggest reduced SP-C leads to
severe RDS
 On-going studies in humans

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SP-C Deficiency
 Presents at a few months of age
 AD mutations in SP-C associated with
Interstitial Lung Disease
 First seen in a family with several siblings
becoming
 Alveolar inflammation, Pulmonary infiltration, loss of
alveolar structure and pulmonary fibrosis
 02 dependent at 3-4 months and developing ILD
and fibrosis

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SP-D
 Role unknown
 Knockout mice develop chronic low grade lung
inflammation and eventual emphysema
 Possibly relevant in development of CLD
 90% of SP-D dissociates from lipids and acts as
soluble opsonin in alveolar lining
 No reports of association with RDS or BPD
 Mutations associated with more severe RSV
infections

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ABCA3 deficiency and Lung Disease
 ATP-binding cassette family
 Lipid transport across membranes
 Expressed in type 2 cells
 Mutation leads to fatal surfactant
deficiency in newborns

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ABCA3 deficiency and Lung Disease
 Desquamative interstitial pneumonitis
Source: Universidad Autonoma de Zacatecas (Mexico)

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Transient Tachypnea of the Newborn
 1-2% of term infants
 O2 requirement and tachypnea
 Risk Factors: Prematurity, C/S, maternal disease, Male,
Twin
 Defective lung liquid clearance after birth
 May have mild surfactant deficiency
 Mutations in the Na Channels or cystic fibrosis
transmembrane conductance regulator (CFTR) may play
a role
 More studies needed

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Cystic Fibrosis
 Mutation in the CFTR gene on Chromosome 7q31.2
 27 coding exons with 6.5 kb mRNA
Source: http://www/genet.sickids.on.ca/PicturePage.html.

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Cystic Fibrosis
 Chloride channel in the cell membrane
 Mutations lead to thick secretions
 Multi-system disorder but primarily pulmonary
with chronic inflammation and infections
 Pancreatic insufficiency, liver disease, biliary
cirrhosis, male infertility (95%)
 1,300 causative mutations found
 33 mutations account for over 90% of cases

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CF Screening
 Echogenic bowel on prenatal U/S (~5%
will be CF)
 Meconium Ileus – nearly pathognomonic
for CF, but only 10-15 of CF patients have
it
 NBS: Immunoreactive trypsin levels
above the 99.5% of population range

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CF Screening
 IRT is a pancreatic enzyme precursor
 Elevated in babies with CF since
pancreatic ducts are partially blocked
 Occurs even if infants are pancreatic
sufficient

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CF Screening
 Reflex CFTR mutation analysis
 Carrier status will be detected
 IRT threshold may miss some CF
patients

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Primary Ciliary Dyskinesia
 Kartagener’s Syndrome
 AR disease occurring in 1 in 15,000 to
20,000 births
 Often mild so many likely
undiagnosed
 Half will have situs inversus (not
dextrocardia alone)

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Source: PCD: Laboratory Heymut Omran, MD University Children's
Hospital Muenster (Germany)

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 Mucus retention in the lung
 Chronic sinusitis, Otitis media,
infertility in males and ectopic
pregnancies in females
 Life expectancy near normal, but
nearly all develop some
bronchiectasis

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 Definitive testing requires nasal cilial brush biopsy
 Ciliary beat frequency assessed (Normal 12.8 hz in children)
 Beat frequency altered by colds
 Sometimes beat patterns ineffective
 Cilia present in the embryonic node and play large role in
laterality
 Mutations thus leave laterality to chance – 50% situs inversus
 Cilia assembled from many different proteins coming from many
different genes
 Three Dynein genes found to lead to PCD, but many more
mutations likely

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Conclusions
 Links between respiratory disease and surfactant components
increase our understanding of pathogenesis of common diseases
 Genetic testing will increase and more rare mutations will be found
 Goal is to identify the particular underlying genetic etiology of
disease
 Allow better prognostication
 Provide for more effective and target treatments
 Identification of novel treatments based on the genetic defect
 Better counseling for future children

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Thank you
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Genetics of Lung Disease

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