HLA-DQB1*05:02, *05:03, and *03:01 alleles as risk factors for myasthenia gravis in a Spanish cohort.

BACKGROUND: Myasthenia gravis (MG) is a very heterogenic chronic autoimmune disease caused by the failure of neuromuscular transmission. The HLA gene complex has conventionally been recognized as its main genetic risk and phenotype modifying factor. Our aim was to investigate the prevalence of HLA class I and II alleles and to identify possible risk factors for sporadic MG in a Spanish cohort. METHODS: We designed a clinical case-control study comparing HLA alleles and haplotype frequencies in a cohort of 234 patients with sporadic autoimmune MG with data from a group of 492 randomly selected healthy subjects. Using a high-resolution next-generation sequencing (NGS)-based HLA genotyping assay, we investigated the contribution of HLA genotypes and haplotypes in the resulting phenotype, especially, the age at onset, sex, onset MGFA class, thymic histopathology, and serological status. RESULTS: We found that the DQB1*05:02 and DQB1*05:03 alleles could be novel risk factors for Spanish MG cases. The HLA alleles A*01:01, B*08:01, DRB1*03:01, DRB1*14:54, and DQB1*02:01 were also risk factors for the disease. DQB1*03:01 acted as a risk factor for EOMG in women with AChR-positive antibodies and thymus hyperplasia. Additionally, several alleles were identified as potential phenotype-modifying factors that could exert a protective effect: HLA-B*35:08, DRB1*13:01, and DQB1*06:03 in MG; HLA-A*24:02 in women and DRB1*07:01 and DQB1*02:02 for early onset. HLA-C*07:01 and haplotype A1-B8-C7-DR3-DQ2 were associated with an early-onset phenotype.

New Cases of Hypochromic Microcytic Anemia Due to Mutations in the SLC11A2 Gene and Functional Characterization of the G75R Mutation.

Divalent metal-iron transporter 1 (DMT1) is a mammalian iron transporter encoded by the SLC11A2 gene. DMT1 has a vital role in iron homeostasis by mediating iron uptake in the intestine and kidneys and by recovering iron from recycling endosomes after transferrin endocytosis. Mutations in SLC11A2 cause an ultra-rare hypochromic microcytic anemia with iron overload (AHMIO1), which has been described in eight patients so far. Here, we report two novel cases of this disease. The first proband is homozygous for a new SLC11A2 splicing variant (c.762 + 35A > G), becoming the first ever patient reported with a SLC11A2 splicing mutation in homozygosity. Splicing studies performed in this work confirm its pathogenicity. The second proband harbors the previously reported DMT1 G75R mutation in homozygosis. Functional studies with the G75R mutation in HuTu 80 cells demonstrate that this mutation results in improper DMT1 accumulation in lysosomes, which correlates with a significant decrease in DMT1 levels in patient-derived lymphoblast cell lines (LCLs). We also suggest that recombinant erythropoietin would be an adequate therapeutic approach for AHMIO1 patients as it improves their anemic state and may possibly contribute to mobilizing excessive hepatic iron.