RESUMO
Germline mutations in FASL and FAS impair Fas-dependent apoptosis and cause recessively or dominantly inherited autoimmune lymphoproliferative syndrome (ALPS). Patients with ALPS typically present with no other clinical phenotype. We investigated a large, consanguineous, multiplex kindred in which biological features of ALPS were found in the context of severe bacterial and viral disease, recurrent hepatopathy and encephalopathy, and cardiac malformations. By a combination of genome-wide linkage and whole-exome sequencing, we identified a homozygous missense mutation in FADD, encoding the Fas-associated death domain protein (FADD), in the patients. This FADD mutation decreases steady-state protein levels and impairs Fas-dependent apoptosis in vitro, accounting for biological ALPS phenotypes in vivo. It also impairs Fas-independent signaling pathways. The observed bacterial infections result partly from functional hyposplenism, and viral infections result from impaired interferon immunity. We describe here a complex clinical disorder, its genetic basis, and some of the key mechanisms underlying its pathogenesis. Our findings highlight the key role of FADD in Fas-dependent and Fas-independent signaling pathways in humans.
Assuntos
Síndrome Linfoproliferativa Autoimune/genética , Éxons , Proteína de Domínio de Morte Associada a Fas/genética , Análise de Sequência de DNA , Sequência de Aminoácidos , Animais , Proteína de Domínio de Morte Associada a Fas/química , Feminino , Humanos , Masculino , Dados de Sequência Molecular , Mutação de Sentido Incorreto , Linhagem , Homologia de Sequência de AminoácidosRESUMO
We describe a novel deletion causing ÎµÎ³Î´ß thalassemia in a Pakistani family. The Pakistani deletion is 506kb in length, and the second largest ÎµÎ³Î´ß thalassemia deletion reported to date. It removes the entire ß globin gene (HBB) cluster, extending from 431kb upstream to 75kb downstream of the ε globin gene (HBE). The breakpoint junction occurred within a 160bp palindrome embedded in LINE/LTR repeats, and contained a short (9bp) region of direct homology which may have contributed to the recombination event. Characterization of the deletion breakpoints has been particularly challenging due to the complexity of DNA deletion, insertion and inversion, involving a multitude of methodologies, mirroring the changing DNA analysis technologies.