title: EIF2AK4 mutations in pulmonary capillary hemangiomatosis.
abstract: BACKGROUND
  Pulmonary capillary hemangiomatosis (PCH) is a rare disease of capillary proliferation of unknown cause and with a high mortality. Families with multiple affected individuals with PCH suggest a heritable cause although the genetic etiology remains unknown.
  
  
  METHODS
  We used exome sequencing to identify a candidate gene for PCH in a family with two affected brothers. We then screened 11 unrelated patients with familial (n = 1) or sporadic (n = 10) PCH for mutations.
  
  
  RESULTS
  Using exome sequencing, we identified compound mutations in eukaryotic translation initiation factor 2 α kinase 4 (EIF2AK4) (formerly known as GCN2) in both affected brothers. Both parents and an unaffected sister were heterozygous carriers. In addition, we identified two EIF2AK4 mutations in each of two of 10 unrelated individuals with sporadic PCH. EIF2AK4 belongs to a family of kinases that regulate angiogenesis in response to cellular stress.
  
  
  CONCLUSIONS
  Mutations in EIF2AK4 are likely to cause autosomal-recessive PCH in familial and some nonfamilial cases.
authors.affiliation: Department of Pathology, The University of Utah, Salt Lake City, UT; ARUP Institute for Clinical and Experimental Pathology, ARUP Laboratories, Salt Lake City, UT.
authors.forename: D Hunter
authors.initials: DH
authors.lastname: Best
authors.affiliation: ARUP Institute for Clinical and Experimental Pathology, ARUP Laboratories, Salt Lake City, UT.
authors.forename: Kelli L
authors.initials: KL
authors.lastname: Sumner
authors.affiliation: Department of Pathology, The University of Utah, Salt Lake City, UT; Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Austin
authors.affiliation: Departments of Pediatrics and Medicine, Columbia University Medical Center, New York, NY.
authors.forename: Wendy K
authors.initials: WK
authors.lastname: Chung
authors.affiliation: Department of Medicine, School of Medicine, and Pulmonary Division, The University of Utah, Salt Lake City, UT; Department of Medicine, Intermountain Medical Center, Intermountain Healthcare, Murray, UT.
authors.forename: Lynette M
authors.initials: LM
authors.lastname: Brown
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY.
authors.forename: Alain C
authors.initials: AC
authors.lastname: Borczuk
authors.affiliation: Departments of Pediatrics and Medicine, Columbia University Medical Center, New York, NY.
authors.forename: Erika B
authors.initials: EB
authors.lastname: Rosenzweig
authors.affiliation: ARUP Institute for Clinical and Experimental Pathology, ARUP Laboratories, Salt Lake City, UT.
authors.forename: Pinar
authors.initials: P
authors.lastname: Bayrak-Toydemir
authors.affiliation: ARUP Institute for Clinical and Experimental Pathology, ARUP Laboratories, Salt Lake City, UT.
authors.forename: Rong
authors.initials: R
authors.lastname: Mao
authors.affiliation: Department of Medicine, The University of Utah, Salt Lake City, UT.
authors.forename: Barbara C
authors.initials: BC
authors.lastname: Cahill
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic Arizona, Mayo Foundation for Medical Education and Research, Scottsdale, AZ.
authors.forename: Henry D
authors.initials: HD
authors.lastname: Tazelaar
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic Arizona, Mayo Foundation for Medical Education and Research, Scottsdale, AZ.
authors.forename: Kevin O
authors.initials: KO
authors.lastname: Leslie
authors.affiliation: Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: Anna R
authors.initials: AR
authors.lastname: Hemnes
authors.affiliation: Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: Ivan M
authors.initials: IM
authors.lastname: Robbins
authors.affiliation: Department of Medicine, School of Medicine, and Pulmonary Division, The University of Utah, Salt Lake City, UT; Department of Medicine, Intermountain Medical Center, Intermountain Healthcare, Murray, UT. Electronic address: greg.elliott@imail.org.
authors.forename: C Gregory
authors.initials: CG
authors.lastname: Elliott
mesh_terms: D000293:Adolescent; D000328:Adult; D002196:Capillaries / Q000473:pathology; D059472:Exome / Q000235:genetics; D005260:Female; D006579:Heterozygote; D006801:Humans; D008171:Lung Diseases / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D016040:Lung Transplantation; D008297:Male; D009154:Mutation / Q000235:genetics*; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D010290:Parents; D010375:Pedigree; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D035781:Siblings; D014652:Vascular Diseases / Q000235:genetics* / Q000473:pathology / Q000601:surgery
chemical_list: C529271:EIF2AK4 protein, human; D017346:Protein Serine-Threonine Kinases