| Autor: |
Córdova-Fletes C; Departamento de Bioquímica y Medicina Molecular, Facultad de Medicina, Universidad Autónoma de Nuevo León, Monterrey, México., Rangel-Sosa MM; Vicerrectoría de Ciencias de la Salud, Departamento de Ciencias Básicas, Universidad de Monterrey, San Pedro Garza García, México., Martínez-Jacobo LA; Vicerrectoría de Ciencias de la Salud, Departamento de Ciencias Básicas, Universidad de Monterrey, San Pedro Garza García, México., Becerra-Solano LE; Unidad de Investigación Médica en Medicina Reproductiva, Hospital de Gineco-Obstetricia No. 4 Luis Castelazo Ayala, IMSS, Ciudad de México, México., Arellano-Valdés CA; Departamento de Medicina Interna y Reumatología pediátrica, UMAE pediatría, CMNO, IMSS, Guadalajara, México., Tlacuilo-Parra JA; Departamento de Medicina Interna y Reumatología pediátrica, UMAE pediatría, CMNO, IMSS, Guadalajara, México., Galán-Huerta KA; Departamento de Bioquímica y Medicina Molecular, Facultad de Medicina, Universidad Autónoma de Nuevo León, Monterrey, México., Rivas-Estilla AM; Departamento de Bioquímica y Medicina Molecular, Facultad de Medicina, Universidad Autónoma de Nuevo León, Monterrey, México., Hernandez-Orozco AA; División de Genética, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social., García-Ortiz JE; División de Genética, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social.; Dirección de Educación e Investigación en Salud, UMAE Hospital de Gineco-Obstretricia, CMNO-IMSS, Guadalajara, México. |
| Abstrakt: |
Blau syndrome (BS) is a rare, chronic autoinflammatory disease with onset before age 4 and mainly characterised by granulomatous arthritis, recurrent uveitis, and skin rash. Sporadic (also known as early-onset sarcoidosis) or familial BS is caused by gain-of-function mutations in the NOD2 gene, which encodes for a multi-task protein that plays a crucial role in the innate immune defense. We report on three Mexican patients clinically diagnosed with BS who exhibited a likely pathogenic variant in NOD2 as revealed by whole-exome sequencing (WES) and Sanger sequencing: two variants (c.1000 C > T/p.Arg334Trp and c.1538 T > C/p.Met513Thr) lie in the ATP/Mg2+ binding site, whereas the other (c.3019dupC/p.Leu1007ProfsTer2) introduces a premature stop codon disrupting the last LRR domain (LRR9) formation; all three variants are consistent with gain-of-function changes. Interestingly, all these patients presented concomitant likely pathogenic variants in other inflammatory disease-related genes, i.e. TLR10 , PRR12 , MEFV and/or SLC22A5 . Although the clinical presentation in these patients included the BS diagnostic triad, overall it was rather heterogeneous. It is plausible that this clinical variability depends partly on the patients' genetic background as suggested by our WES results. After this molecular diagnosis and given the absence of NOD2 mutations (demonstrated in two trios) and related symptoms in the respective parents (confirmed in all trios), patients 1 and 2 were considered to have sporadic BS, while patient 3, a sporadic BS-recurrent polyserositis compound phenotype. Altogether, our observations and findings underscore the overlapping among inflammatory diseases and the importance of determining the underlying genetic cause by high-throughput methods. Likewise, this study further reinforces a pathogenic link between the here found NOD2 variants and BS and envisages potential additive effects from other loci in these, and probably other patients. |
