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Original Research: Pulmonary Vascular Disease |

EIF2AK4 Mutations in Pulmonary Capillary HemangiomatosisMutations in Pulmonary Capillary Hemangiomatosis

D. Hunter Best, PhD; Kelli L. Sumner, BS; Eric D. Austin, MD; Wendy K. Chung, MD, PhD; Lynette M. Brown, MD, PhD; Alain C. Borczuk, MD; Erika B. Rosenzweig, MD; Pinar Bayrak-Toydemir, MD, PhD; Rong Mao, MD; Barbara C. Cahill, MD; Henry D. Tazelaar, MD, FCCP; Kevin O. Leslie, MD; Anna R. Hemnes, MD; Ivan M. Robbins, MD; C. Gregory Elliott, MD, FCCP
Author and Funding Information

From the Department of Pathology (Drs Best, Bayrak-Toydemir, and Mao) and Department of Medicine (Drs Brown and Elliott), School of Medicine, and Pulmonary Division and Department of Medicine (Dr Cahill), The University of Utah, Salt Lake City, UT; ARUP Institute for Clinical and Experimental Pathology (Drs Best, Bayrak-Toydemir, and Mao and Ms Sumner), ARUP Laboratories, Salt Lake City, UT; Department of Pediatrics (Dr Austin) and Division of Allergy, Pulmonary and Critical Care Medicine (Drs Hemnes and Robbins), Vanderbilt University Medical Center, Nashville, TN; Departments of Pediatrics and Medicine (Drs Chung and Rosenzweig) and Department of Pathology and Cell Biology (Dr Borczuk), Columbia University Medical Center, New York, NY; Department of Medicine (Drs Brown and Elliott), Intermountain Medical Center, Intermountain Healthcare, Murray, UT; and Department of Laboratory Medicine and Pathology (Drs Tazelaar and Leslie), Mayo Clinic Arizona, Mayo Foundation for Medical Education and Research, Scottsdale, AZ.

Correspondence to: C. Gregory Elliott, MD, FCCP, Department of Medicine, Intermountain Medical Center, 5121 S Cottonwood St, #307, Murray, UT 84107; e-mail: greg.elliott@imail.org


For editorial comment see page 197

Funding/Support: This research was supported in part by the National Institutes of Health [K23 HL098743; R01 HL060056; NIH 1P01HL108800-0] and Intermountain Research and Medical Foundation [1007044].

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;145(2):231-236. doi:10.1378/chest.13-2366
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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.

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