Monoallelic expression can govern penetrance of inborn errors of immunity

• 成果类型: Article
• 署名作者: Stewart, O'Jay; Gruber, Conor; Randolph, Haley E.; Patel, Roosheel; Ramba, Meredith; Calzoni, Enrica; Huang, Lei Haley; Levy, Jay; Buta, Sofija; Lee, Angelica; Sazeides, Christos; Prue, Zoe; van Konijnenburg, David P. Hoytema; Chinn, Ivan K.; Pedroza, Luis A.; Lupski, James R.; Schmitt, Erica G.; Cooper, Megan A.; Puel, Anne; Peng, Xiao; Boisson-Dupuis, Stephanie; Bustamante, Jacinta; Okada, Satoshi; Martin-Fernandez, Marta; Orange, Jordan S.; Casanova, Jean-Laurent; Milner, Joshua D.; Bogunovic, Dusan
• 署名单位: Columbia University; Columbia University; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Columbia University; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Harvard Medical School; Harvard University; Harvard Medical School; Baylor College of Medicine; Baylor College of Medicine; Baylor College Medical Hospital; Baylor College of Medicine; Baylor College of Medicine; St. Louis Children's Hospital; Washington University (WUSTL); Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Paris Cite; Universite Paris Cite; Institut National de la Sante et de la Recherche Medicale (Inserm); Assistance Publique Hopitaux Paris (APHP); Universite Paris Cite; Hopital Universitaire Necker-Enfants Malades - APHP; Johns Hopkins University; Rockefeller University; Hiroshima University; Instituto de Salud Carlos III; Instituto de Investigacion de Enfermedades Raras (IIER); Howard Hughes Medical Institute; Assistance Publique Hopitaux Paris (APHP); Universite Paris Cite; Hopital Universitaire Necker-Enfants Malades - APHP
• 刊物名称: Nature
• ISSN/ISSBN: 0028-2690
• DOI: 10.1038/s41586-024-08346-4
• 发表日期: 2025-01-30
• 关键词: gene-expression; allelic expression; x-chromosome; mutations; inactivation; mouse; immunodeficiency; mycobacterial; landscape; phenotype

摘要

Inborn errors of immunity (IEIs) are genetic disorders that underlie susceptibility to infection, autoimmunity, autoinflammation, allergy and/or malignancy1. Incomplete penetrance is common among IEIs despite their monogenic basis2. Here we investigate the contribution of autosomal random monoallelic expression (aRMAE), a somatic commitment to the expression of one allele3,4, to phenotypic variability observed in families with IEIs. Using a clonal primary T cell system to assess aRMAE status of genes in healthy individuals, we find that 4.30% of IEI genes and 5.20% of all genes undergo aRMAE. Perturbing H3K27me3 and DNA methylation alters allele expression commitment, in support of two proposed mechanisms5,6 for the regulation of aRMAE. We tested peripheral blood mononuclear cells from individuals with IEIs with shared genetic lesions but discordant clinical phenotypes for aRMAE. Among two relatives who were heterozygous for a mutation in PLCG2 (delEx19), an antibody deficiency phenotype corresponds to selective mutant allele expression in B cells. By contrast, among relatives who were heterozygous for a mutation in JAK1 (c.2099G>A; p.S700N), the unaffected carrier T cells predominantly expressed the wild-type JAK1 allele, whereas the affected carrier T cells exhibited biallelic expression. Allelic expression bias was also documented in phenotypically discordant family members with mutations in STAT1 and CARD11. This study highlights the importance of considering both the genotype and the 'transcriptotype' in analyses of the penetrance and expressivity of monogenic disorders.