Project description:TFRC, also known as CD71, regulates the uptake of transferrin-bound iron into cells through receptor-mediated endocytosis. In a patient with a combined immunodeficiency, we identified a homozygous missense mutation in TFRC gene leading to R22W amino acid change in the cytoplasmic tail of the receptor. This mutation impairs the endocytosis of TFRC, which results in profound aberrations in the immune system.
Project description:IKKα is a critical regulator of the non-canonical NF-KB signalling pathway. In patients with combined immunodeficiency, we identified a homozygous missense mutation in CHUK gene, coding for IKKα protein, leading to G167R amino acid change in the kinase domain of the protein. This mutation impairs the kinase activity of IKKα, which results in a range of aberratins in innate and adaptive immunity.
Project description:IKKα, encoded by CHUK, is crucial in the non-canonical NF-κB pathway and part of the IKK complex activating the canonical pathway alongside IKKβ. The absence of IKKα causes fetal encasement syndrome in humans, fatal in utero, while an impaired IKKα-NIK interaction was reported in a single patient and causes combined immunodeficiency. Here, we describe compound heterozygous variants in the kinase domain of IKKα in a female patient with hypogammaglobulinemia, recurrent lung infections, and Hay-Wells syndrome-like features. We showed that both variants were loss-of-function. Non-canonical NF-κB activation was profoundly diminished in stromal and immune cells while the canonical pathway was unexpectedly partially impaired. Reintroducing wt CHUK restored non-canonical NF-κB activation. The patient had neutralizing autoantibodies against type I IFN, akin to non-canonical NF-κB pathway deficiencies. Thus, this is the first case of biallelic CHUK mutations disrupting IKKα kinase function, broadening non-canonical NF-κB defect understanding, and suggesting IKKα's role in canonical NF-κB target gene expression in humans.
Project description:SIFD (Congenital sideroblastic anemia, B-cell immunodeficiency, Periodic fevers and Developmental delay) Syndrome is caused by biallelic mutations in tRNA nucleotidyltransferase CCA-adding, 1 (TRNT1) gene. The onset of the disease is usually neonatal or in early infancy and the clinical presentation is widely heterogeneous. Myelodysplastic syndromes (MDS) with ring sideroblasts, which is characterised by somatic mutations in SF3B1 gene in more than 80% of cases, have never been reported as associated with SIFD Syndrome. Here we report a case of an adult male patient with a novel non-sense heterozygous mutation in TRNT1 gene, which developed MDS with somatic K700E SF3B1 mutation and trisomy 8. WES revealed additional somatic variations affecting genes implicated in cell proliferation, apoptosis and DNA mismatch repair: ARID1A, HERC1, IL4R, TMEM260 and CDKL3. Besides the typical recurrent aseptic pneumonias and sinopulmonary bacterial infections, he developed lymphohistiocytic subcutaneous panniculitis and subsequently a subcutaneous panniculitis-like T-cell lymphoma (SPTCL), suggesting that predisposition in the TRNT1 positive syndrome extends to both lymphoid and myeloid neoplasms. This report is particularly relevant to provide insights on the hematological impact of TRNT1 positive syndrome in adults and to improve early diagnosis and management of this rare disease.
Project description:We are interested in deciphering the mechanism by which DNA methylation in late B cell differentiation affects humoral immune response. We were using enzymatic-methyl sequencing (EM-seq) and chose to study a very rare immunodeficiency called ICF type 4, where a point mutation in a gene encoding the protein HELLS causes a lack of both circulating antibodies and memory B cells in human. HELLS is a chromatin remodeler, that allows for DNA methylation to occur.