Chinami Hashimura

Mutation of DNASE1 in people with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a highly prevalent human autoimmune diseases that causes progressive glomerulonephritis, arthritis and an erythematoid rash. Mice deficient in deoxyribonuclease I (Dnase1) develop an SLE-like syndrome. Here we describe two patients with a heterozygous nonsense mutation in exon 2 of DNASE1, decreased DNASE1 activity and an extremely high immunoglobulin G titer against nucleosomal antigens. These data are consistent with the hypothesis that a direct connection exists between low activity of DNASE1 and progression of human SLE.

Association of MBL gene polymorphisms with major bacterial infection in patients treated with high-dose chemotherapy and autologous PBSCT

A growing body of evidence indicates that genetic factors are involved in an increased risk of infection. We investigated whether mannose-binding lectin (MBL) gene polymorphisms that cause low levels of MBL are associated with the occurrence of major infections in patients, mainly bearing hematological malignancies, after high-dose chemotherapy (HDT) rescued by autologous peripheral blood stem cell transplantation (auto-PBSCT). A retrospective evaluation of 113 patients treated with HDT and auto-PBSCT revealed that the low-producing genotypes, B/B and B/LXA, were associated with major bacterial infection (P=0.0016, OR 7.9). We next performed a nation-wide large-scale study to assess the allele frequency of the MBL coding mutation in a total of 2623 healthy individuals in Japan. The frequency of allele B was estimated to be ∼0.2, almost the same in seven different areas of Japan. This common occurrence suggests that MBL deficiency may play an important role in the clinical settings of immunosuppression.

MANNOSE BINDING LECTIN (MBL) GENE MUTATION IS NOT A RISK FACTOR FOR SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) AND RHEUMATOID ARTHRITIS (RA) IN JAPANESE

Mannose binding lectin (MBL) deficiency may be associated with increased susceptibility to infection and autoimmune disorders, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). In the present study, we performed for the first systematic search for mutations in all the four exons of the MBL gene using polymerase chain reaction (PCR)/single-strand conformation polymorphism (SSCP) analysis. Of 49 healthy Japanese individuals studied, only the previously reported mutation at the codon 54 (substitution from Gly to Asp; G54D) was identified. The allele frequencies of G54D in 105 healthy Japanese individuals, 95 SLE patients and 59 RA patients, were 0.233, 0.226 and 0.178, respectively, which were not significantly different. In addition, two polymorhisms at positions of −550 and −221 in the promoter region were not associated with SLE and RA. It is unlikely that MBL deficiency plays a major role in the pathogenesis of SLE and RA in Japanese.

A novel nonsense mutation at Glu-631 in a Spanish family with complement component 7 deficiency

AbstractDeficiency of the seventh component of complement (C7D) is frequently associated with recurrent neisserial infections. We report in the present study the genetic basis for C7D in a Spanish family. We used exon-specific polymerase chain reaction (PCR)/single-strand conformation polymorphism (SSCP) analysis as a screening step for mutations, followed by direct sequencing of the target exon. The mutation in the proband was a homozygous G-to-T transversion at nucleotide 1957, the first nucleotide of the codon GAG for Glu-631, leading to a stop codon TAG (E631X). Our result provides further evidence that the molecular pathogenesis of C7D is heterogeneous.

A missense mutation of the plasminogen gene in hereditary angioedema with normal C1 inhibitor in Japan

more toxic drugs in case of relapse. The study was approved by the Internal Review Board of the Clinic. The baseline features of the study patients along with the clinical response to the treatment are shown in Table 1. Seven of 14 patients (50%) showed an ongoing complete control of the disease (UAS7 < 6) despite halving the monthly dose of omalizumab. In the remaining seven patients, the dose reduction was associated with a worsening of the disease (UAS7 score between 7 and 21), although in no case, it returned to the baseline severity. The partial loss of response to the drug did not depend on disease duration, the presence of thyroid autoimmunity, or baseline ESR, CRP, or D‐dimer, whereas it was associated with the baseline severity of the disease (P < 0.05). Also, a history of angioedema was much more frequent among those who worsened following the reduction in omalizumab dosage (6/7, 86%) than in patients who maintained the control of the disease (2/7; 29%), but due to the small number of patients, the difference did not reach the statistical significance. Although studies on larger number of patients are needed to confirm these observations and despite the limitation of being nonrandomized, the present real‐life study suggests that it is possible to halve the costs of omalizumab maintenance treatment in about one half of patients with severe CSU showing a prompt response to the drug at the dose of 300 mg/mo without any loss of clinical efficacy. Patients who worsen with a reduced dosage of omalizumab are in general those showing a more severe diseases at baseline as well as those with a history of angioedema associated with the wheals. This is in keeping with previous observations that in patients with angioedema, only the dosage of 300 mg/month seems to be effective 2 Whether the reduction in omalizumab dosage as a maintenance therapy will work also in patients showing a delayed response to the drug remains to be established. In conclusion, this study confirms previous observations in a very small number of patients 10 that a maintenance monthly dose of 150 mg of omalizumab may be sufficient to guarantee an ongoing control of the disease in a large proportion of patients with CSU showing an early response to the drug.