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- Keller, Baerbel, et al.
(författare)
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Early onset combined immunodeficiency and autoimmunity in patients with loss-of-function mutation in LAT
- 2016
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Ingår i: Journal of Experimental Medicine. - : ROCKEFELLER UNIV PRESS. - 0022-1007 .- 1540-9538. ; 213:7, s. 1185-1199
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Tidskriftsartikel (refereegranskat)abstract
- The adapter protein linker for activation of T cells (LAT) is a critical signaling hub connecting T cell antigen receptor triggering to downstream T cell responses. In this study, we describe the first kindred with defective LAT signaling caused by a homozygous mutation in exon 5, leading to a premature stop codon deleting most of the cytoplasmic tail of LAT, including the critical tyrosine residues for signal propagation. The three patients presented from early childhood with combined immunodeficiency and severe autoimmune disease. Unlike in the mouse counterpart, reduced numbers of T cells were present in the patients. Despite the reported nonredundant role of LAT in Ca2+ mobilization, residual T cells were able to induce Ca2+ influx and nuclear factor (NF) kappa B signaling, whereas extracellular signal-regulated kinase (ERK) signaling was completely abolished. This is the first report of a LAT-related disease in humans, manifesting by a progressive combined immune deficiency with severe autoimmune disease.
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- Spiegel, Ronen, et al.
(författare)
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Deleterious mutation in FDX1L gene is associated with a novel mitochondrial muscle myopathy
- 2014
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Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 22:7, s. 902-906
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Tidskriftsartikel (refereegranskat)abstract
- Isolated metabolic myopathies encompass a heterogeneous group of disorders, with mitochondrial myopathies being a subgroup, with depleted skeletal muscle energy production manifesting either by recurrent episodes of myoglobinuria or progressive muscle weakness. In this study, we investigated the genetic cause of a patient from a consanguineous family who presented with adolescent onset autosomal recessive mitochondrial myopathy. Analysis of enzyme activities of the five respiratory chain complexes in our patients' skeletal muscle showed severely impaired activities of iron sulfur (Fe-S)-dependent complexes I, II and III and mitochondrial aconitase. We employed exome sequencing combined with homozygosity mapping to identify a homozygous mutation, c.1A > T, in the FDX1L gene, which encodes the mitochondrial ferredoxin 2 (Fdx2) protein. The mutation disrupts the ATG initiation translation site resulting in severe reduction of Fdx2 content in the patient muscle and fibroblasts mitochondria. Fdx2 is the second component of the Fe-S cluster biogenesis machinery, the first being IscU that is associated with isolated mitochondrial myopathy. We suggest adding genetic analysis of FDX1L in cases of mitochondrial myopathy especially when associated with reduced activity of the respiratory chain complexes I, II and III.
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