TY  - JOUR
A1  - Van Haute, Lindsey
A1  - Dietmann, Sabine
A1  - Kremer, Laura
A1  - Hussain, Shobbir
A1  - Pearce, Sarah F.
A1  - Powell, Christopher A.
A1  - Rorbach, Joanna
A1  - Lantaff, Rebecca
A1  - Blanco, Sandra
A1  - Sauer, Sascha
A1  - Kotzaeridou, Urania
A1  - Hoffmann, Georg F.
A1  - Memari, Yasin
A1  - Kolb-Kokocinski, Anja
A1  - Durbin, Richard
A1  - Mayr, Johannes A.
A1  - Frye, Michaela
A1  - Prokisch, Holger
A1  - Minczuk, Michal
T1  - Deficient methylation and formylation of mt-tRNA(Met) wobble cytosine in a patient carrying mutations in NSUN3
JF  - Nature Communications
N2  - Epitranscriptome modifications are required for structure and function of RNA and defects in these pathways have been associated with human disease. Here we identify the RNA target for the previously uncharacterized 5-methylcytosine (m5C) methyltransferase NSun3 and link m5C RNA modifications with energy metabolism. Using whole-exome sequencing, we identified loss-of-function mutations in NSUN3 in a patient presenting with combined mitochondrial respiratory chain complex deficiency. Patient-derived fibroblasts exhibit severe defects in mitochondrial translation that can be rescued by exogenous expression of NSun3. We show that NSun3 is required for deposition of m5C at the anticodon loop in the mitochondrially encoded transfer RNA methionine (mt-tRNAMet). Further, we demonstrate that m5C deficiency in mt-tRNAMet results in the lack of 5-formylcytosine (f5C) at the same tRNA position. Our findings demonstrate that NSUN3 is necessary for efficient mitochondrial translation and reveal that f5C in human mitochondrial RNA is generated by oxidative processing of m5C.
KW  - Methylation
KW  - RNA
KW  - Transferases
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165998
VL  - 7
ER  - 
TY  - JOUR
A1  - Lenz, Dominic
A1  - Pahl, Jens
A1  - Hauck, Fabian
A1  - Alameer, Seham
A1  - Balasubramanian, Meena
A1  - Baric, Ivo
A1  - Boy, Nikolas
A1  - Church, Joseph A.
A1  - Crushell, Ellen
A1  - Dick, Anke
A1  - Distelmaier, Felix
A1  - Gujar, Jidnyasa
A1  - Indolfi, Giuseppe
A1  - Lurz, Eberhard
A1  - Peters, Bianca
A1  - Schwerd, Tobias
A1  - Serranti, Daniele
A1  - Kölker, Stefan
A1  - Klein, Christoph
A1  - Hoffmann, Georg F.
A1  - Prokisch, Holger
A1  - Greil, Johann
A1  - Cerwenka, Adelheid
A1  - Giese, Thomas
A1  - Staufner, Christian
T1  - NBAS Variants Are Associated with Quantitative and Qualitative NK and B Cell Deficiency
JF  - Journal of Clinical Immunology
N2  - Purpose
Biallelic pathogenic NBAS variants manifest as a multisystem disorder with heterogeneous clinical phenotypes such as recurrent acute liver failure, growth retardation, and susceptibility to infections. This study explores how NBAS-associated disease affects cells of the innate and adaptive immune system.

Methods
Clinical and laboratory parameters were combined with functional multi-parametric immunophenotyping methods in fifteen NBAS-deficient patients to discover possible alterations in their immune system.

Results
Our study revealed reduced absolute numbers of mature CD56dim natural killer (NK) cells. Notably, the residual NK cell population in NBAS-deficient patients exerted a lower potential for activation and degranulation in response to K562 target cells, suggesting an NK cell–intrinsic role for NBAS in the release of cytotoxic granules. NBAS-deficient NK cell activation and degranulation was normalized upon pre-activation by IL-2 in vitro, suggesting that functional impairment was reversible. In addition, we observed a reduced number of naïve B cells in the peripheral blood associated with hypogammaglobulinemia.

Conclusion
In summary, we demonstrate that pathogenic biallelic variants in NBAS are associated with dysfunctional NK cells as well as impaired adaptive humoral immunity.
KW  - NBAS
KW  - inborn error of immunity
KW  - NK cell deficiency
KW  - B cell deficiency
KW  - vesicle trafficking
KW  - familial hemophagocytic lymphohistiocytosis
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-308362
SN  - 0271-9142
SN  - 1573-2592
VL  - 41
IS  - 8
ER  -