Project description:<p>We describe four patients from two unrelated families of different ethnicities who had primary immunodeficiency predominantly manifesting as susceptibility to EBV-related diseases. We performed whole exome sequencing (P1 and P2 from family 1) or whole genome sequencing (P4 and both parents from family 2) in those two families and identified homozygous frameshift or in-frame deletions in CD70 in these patients which abolished either CD70 surface expression or binding to its counter structure CD27. Sanger sequencing identified the same homozygous <i>CD70</i> mutation in P3, which is not included in the dbGaP submission. Autosomal recessive CD70 deficiency is a novel cause of combined immunodeficiency and EBV-associated diseases, reminiscent of CD27 deficiency.</p>
Project description:The autosomal recessive immuno-osseus dysplasia spondyloenchondrodysplasia (SPENCD) is characterised by the variable combination of metaphyseal and vertebral bone lesions, immune dysfunction with features of both autoimmunity and immunodeficiency, and neurological involvement including developmental delay and spasticity with intracranial calcification and leukodystrophy. This transcription profiling study of blood compared four patients to two control subjects. A deficiency of ACP5 encoding tartrate resistant acid phosphatase (TRAP) was found to cause this skeletal dysplasia demonstrating a type I interferon signature with autoimmunity.
Project description:<p>To define a genetic syndrome of combined immunodeficiency, severe autoimmunity, and developmental delay, 4 patients from two families who had similar syndromic features were studied. To identify disease-causing mutations, we performed whole exome sequencing for one patient and her healthy parent from Family 1 and also for one patient from Family 2. Disease segregated with novel autosomal recessive mutations in a single gene, tripeptidyl-peptidase II (<i>TPP2</i>) gene. The result defines a new human metabolic immunodeficiency.</p>
Project description:Ataxia telangiectasia mutated (ATM) is a protein that belongs to the family of phosphatidylinositol 3-kinase (PI3K)-like serine/threonine kinases. Initially identified as a nuclear protein essential for the DNA damage response (DDR) in mitotic cells, it serves as repair coordinator for DNA double-strand breaks (DSBs). Dysfunction of the ATM protein underlies ataxia telangiectasia (A-T), a rare autosomal recessive disorder characterized by immunodeficiency and progressive cerebellar degeneration leading to ataxia. The cause of cerebellar neurodegeneration cannot be explained at present, given that in postmitotic neurons ATM has a cytoplasmic localization. The non-nuclear functions of ATM and their mechanistic link to cerebellar degeneration in A-T remain elusive. In this study we established both phosphoproteomic and proteomic profiles of ATM deficiency in neuroblastoma cells and mouse cerebellum tissue to identify the underlying molecular mechanism and relevant signaling networks.
