Spectrum of Phenotypes Associated with Mutations in LRBA

Alkhairy, Omar K.; Abolhassani, Hassan; Rezaei, Nima; Fang, Mingyan; Andersen, Kasper Krogh; Chavoshzadeh, Zahra; Mohammadzadeh, Iraj; El-Rajab, Mariam; Massaad, Michel J.; Chou, Janet; Aghamohammadi, Asghar; Geha, Raif S.; Hammarström, Lennart

doi:10.1007/s10875-015-0224-7

Cited by 180 publications

(238 citation statements)

References 142 publications

(176 reference statements)

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“…Lrba, a gene known to cause common variable immunodeficiency with autoimmunity-8 (CVID8) [Online Mendelian Inheritance in Man (OMIM) ID no. 614700] and IBD in humans (13)(14)(15), was also mapped by this method, validating our screen as a means to identify human disease genes and components…”

supporting

confidence: 56%

Creatine maintains intestinal homeostasis and protects against colitis

Turer

McAlpine

Wang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Creatine, a nitrogenous organic acid, replenishes cytoplasmic ATP at the expense of mitochondrial ATP via the phosphocreatine shuttle. Creatine levels are maintained by diet and endogenous synthesis from arginine and glycine. Glycine amidinotransferase (GATM) catalyzes the rate-limiting step of creatine biosynthesis: the transfer of an amidino group from arginine to glycine to form ornithine and guanidinoacetate. We screened 36,530 third-generation germline mutant mice derived from N-ethyl-N-nitrosourea–mutagenized grandsires for intestinal homeostasis abnormalities after oral administration of dextran sodium sulfate (DSS). Among 27 colitis susceptibility phenotypes identified and mapped, one was strongly correlated with a missense mutation in Gatm in a recessive model of inheritance, and causation was confirmed by CRISPR/Cas9 gene targeting. Supplementation of homozygous Gatm mutants with exogenous creatine ameliorated the colitis phenotype. CRISPR/Cas9-targeted (Gatmc/c) mice displayed a normal peripheral immune response and immune cell homeostasis. However, the intestinal epithelium of the Gatmc/c mice displayed increased cell death and decreased proliferation during DSS treatment. In addition, Gatmc/c colonocytes showed increased metabolic stress in response to DSS with higher levels of phospho-AMPK and lower levels of phosphorylation of mammalian target of rapamycin (phospho-mTOR). These findings establish an in vivo requirement for rapid replenishment of cytoplasmic ATP within colonic epithelial cells in the maintenance of the mucosal barrier after injury.

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supporting

confidence: 56%

Creatine maintains intestinal homeostasis and protects against colitis

Turer

McAlpine

Wang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…(CVID-8, MIM #614700)(7) which often includes early-onset autoimmunity, immune dysregulation, recurrent infections and hypogammaglobinaemia with variable penetrance (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)27). Neonatal diabetes had not been confirmed as a feature of this disorder.…”

Section: Discussionmentioning

confidence: 99%

Recessively InheritedLRBAMutations Cause Autoimmunity Presenting as Neonatal Diabetes

et al. 2017

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Young-onset autoimmune diabetes associated with additional autoimmunity usually reflects a polygenic predisposition but rare cases result from monogenic autoimmunity. Diagnosing monogenic autoimmunity is crucial for patients' prognosis and clinical management. We sought to identify novel genetic causes of autoimmunity presenting with neonatal diabetes (NDM; diagnosis <6 months).We performed exome sequencing in a patient with NDM and autoimmune lymphoproliferative syndrome and his unrelated, unaffected parents and identified compound heterozygous null mutations in LRBA. Biallelic LRBA mutations cause Common Variable Immunodeficiency-8, however NDM has not been confirmed in this disorder.We sequenced LRBA in 169 additional

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“…According to previously published studies, clinical features in patients with LRBA deficiency are heterogeneous, and first presentations of the disease often occur during childhood (2). The cohort study of Alkhairy et al (2) divided the disease phenotypes into categories of RTI, autoimmunity, organomegaly, and enteropathy.…”

Section: Discussionmentioning

confidence: 99%

“…This disorder is characterized by early-onset hypogammaglobulinemia, chronic diarrhea and autoimmune manifestations (1)(2)(3)(4). Similar to common variable immune deficiency (CVID) patients, affected individuals show a reduced levels of immunoglobulin (Ig) isotypes and suffer from recurrent infections, hepatosplenomegaly, chronic pulmonary disorders as well as auto-inflammatory conditions including idiopathic thrombocytopenic purpura (ITP), autoimmune hemolytic anemia (AIHA) and enteropathy (1,(5)(6)(7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

“…The enteropathy phenotype includes autoimmune enteropathy, inflammatory bowel disease (IBD)/IBD-like disease and non-infectious recurrent diarrhea. LRBA deficiency has been reported to be common among patients with CVID-like phenotype underwent genetic diagnosis (2,10,11). CVID patients and patients with LRBA deficiency resemble symptoms of enteropathy presenting in immunocompetent individuals, but the pathology is usually documented to be not similar and the symptoms often do not respond to the conventional therapies.…”

Section: Introductionmentioning

confidence: 99%

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