A Human Hereditary Cardiomyopathy Shares a Genetic Substrate With Bicuspid Aortic Valve.

BACKGROUND: The complex genetics underlying human cardiac disease is evidenced by its heterogenous manifestation, multigenic basis, and sporadic occurrence. These features have hampered disease modeling and mechanistic understanding. Here, we show that 2 structural cardiac diseases, left ventricular noncompaction (LVNC) and bicuspid aortic valve, can be caused by a set of inherited heterozygous gene mutations affecting the NOTCH ligand regulator MIB1 (MINDBOMB1) and cosegregating genes. METHODS: We used CRISPR-Cas9 gene editing to generate mice harboring a nonsense or a missense MIB1 mutation that are both found in LVNC families. We also generated mice separately carrying these MIB1 mutations plus 5 additional cosegregating variants in the ASXL3, APCDD1, TMX3, CEP192, and BCL7A genes identified in these LVNC families by whole exome sequencing. Histological, developmental, and functional analyses of these mouse models were carried out by echocardiography and cardiac magnetic resonance imaging, together with gene expression profiling by RNA sequencing of both selected engineered mouse models and human induced pluripotent stem cell-derived cardiomyocytes. Potential biochemical interactions were assayed in vitro by coimmunoprecipitation and Western blot. RESULTS: Mice homozygous for the MIB1 nonsense mutation did not survive, and the mutation caused LVNC only in heteroallelic combination with a conditional allele inactivated in the myocardium. The heterozygous MIB1 missense allele leads to bicuspid aortic valve in a NOTCH-sensitized genetic background. These data suggest that development of LVNC is influenced by genetic modifiers present in affected families, whereas valve defects are highly sensitive to NOTCH haploinsufficiency. Whole exome sequencing of LVNC families revealed single-nucleotide gene variants of ASXL3, APCDD1, TMX3, CEP192, and BCL7A cosegregating with the MIB1 mutations and LVNC. In experiments with mice harboring the orthologous variants on the corresponding Mib1 backgrounds, triple heterozygous Mib1 Apcdd1 Asxl3 mice showed LVNC, whereas quadruple heterozygous Mib1 Cep192 Tmx3;Bcl7a mice developed bicuspid aortic valve and other valve-associated defects. Biochemical analysis suggested interactions between CEP192, BCL7A, and NOTCH. Gene expression profiling of mutant mouse hearts and human induced pluripotent stem cell-derived cardiomyocytes revealed increased cardiomyocyte proliferation and defective morphological and metabolic maturation. CONCLUSIONS: These findings reveal a shared genetic substrate underlying LVNC and bicuspid aortic valve in which MIB1-NOTCH variants plays a crucial role in heterozygous combination with cosegregating genetic modifiers.

La interleucina 10 en enfermedades reumáticas autoinmunes / The interleukin 10 in autoimmunity rheumatic diseases

Muchas enfermedades reumáticas autoinmunes se caracterizan por hiperreactividad de sus linfocitos B que resulta en hipergammaglobulinemia y emergencia de autoanticuerpos. Recientemente se ha demostrado que la IL-10 es uno de los más potentes activadores de los linfocitos B. Induce en ellos proliferación y síntesis de inmunoglubulinas. La IL-10 también es capaz de prolongar la supervivencia de los linfocitos B al inducir en ellos la producción de bcl-2 y así protegerlos de la muerte celular programada. La IL-10 puede tener un papel importante en el desarrollo de linfomas B, particularmente en el contexto de una replicación anormal del virus de Epstein-Barr. En artritis reumatoide, síndrome de Sjögren y lupus eritematoso existe una alteración de la regulación genética de la IL-10. Esta alteración se observa en linfocitos B y monocitos. El resultado de esa anormalidad conduce a la estimulación de los linfocitos B por vía autócrina y parácrina. En este artículo revisamos los mecanismos de la regulación genética de la IL-10 y su papel en enfermedades reumáticas autoinmunes. Proponemos, además, nuevas modalidades terapéuticas que pudieran modular los efectos de la IL-10 en estas enfermedades