EIF2AK4 mutations in pulmonary capillary hemangiomatosis.

Best DH, Sumner KL, Austin ED, Chung WK, Brown LM, Borczuk AC, Rosenzweig EB, Bayrak-Toydemir P, Mao R, Cahill BC, Tazelaar HD, Leslie KO, Hemnes AR, Robbins IM, Elliott CG
Chest. 2014 145 (2): 231-236

PMID: 24135949 · PMCID: PMC3921094 · DOI:10.1378/chest.13-2366

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.

MeSH Terms (17)

Adolescent Adult Capillaries Exome Female Heterozygote Humans Lung Diseases Lung Transplantation Male Mutation Neovascularization, Pathologic Parents Pedigree Protein-Serine-Threonine Kinases Siblings Vascular Diseases

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