Highly variable clinical phenotypes of hypomorphic RAG1 mutations.
Hypomorphic mutations that lead to "leaky" severe combined immunodeficiency presentation with partial protein function are increasingly being identified. Mutations in recombination-activating genes (RAGs) 1 and 2 cause immunodeficiency and dysregulation ranging from severe combined immunodeficiency to Omenn syndrome to more mild immunodeficiencies. We report here the cases of 3 patients with hypomorphic RAG1 mutations with distinct presentations. One patient had granulomatous skin disease and disseminated nontuberculous mycobacteria; the second patient presented with predominantly autoimmune manifestations; and the third patient presented with relatively late onset of infections and had isolated T-cell lymphopenia. These disparate and atypical presentations of hypomorphic RAG1 mutations highlight the role of RAG1 in immune function and autoimmunity and expand the disease spectrum linked to these genes.
Avila
Elizabeth Mannino
EM
Duke University School of Medicine, Durham, North Carolina, USA.
Uzel
Gulbu
G
Hsu
Amy
A
Milner
Joshua D
JD
Turner
Maria L
ML
Pittaluga
Stefania
S
Freeman
Alexandra F
AF
Holland
Steven M
SM
D000483:Alleles; D001327:Autoimmune Diseases / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology; D018791:CD4 Lymphocyte Count; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D017809:Fatal Outcome; D005260:Female; D006580:Genetic Carrier Screening; D006105:Granulomatous Disease, Chronic / Q000175:diagnosis / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007223:Infant; D008231:Lymphopenia / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology; D008297:Male; D015270:Mycobacterium avium-intracellulare Infection / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology; D009894:Opportunistic Infections / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology; D010641:Phenotype; D016511:Severe Combined Immunodeficiency / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
D018398:Homeodomain Proteins; C064658:RAG-1 protein