A Missense Mutation of the Plasminogen Gene in a Japanese Family with Hereditary Angioedema with Normal C1 Inhibitor: Third Family Survey in Asia.

Hereditary angioedema (HAE) is a life-threatening disease associated with recurrent episodes of subcutaneous and mucosal swelling, painful abdominal cramping, and asphyxiation. HAE has long been thought to be caused by genetic defects of C1 inhibitors (C1-INH). Recently, HAE with a normal C1 inhibitor expression (HAEnCI) was reported, and the missense mutation p.Lys330Glu (K330E) in exon 9 of the plasminogen (PLG) gene was shown to be responsible for a subset of HAEnCI. HAE with the K330E mutation in the PLG gene-PLG (HAE-PLG) has been reported in only two Japanese families in Asia. We herein report a third family with HAE-PLG in Japan.

Prevalence of dyslipidemia in Japanese patients with rheumatoid arthritis and effects of atorvastatin treatment.

Few studies have examined dyslipidemia in patients with rheumatoid arthritis (RA), especially in Japanese cohorts. The aims of this study were to investigate the lipid profiles of RA patients, to assess the relationships between lipid profiles and RA activity and treatment, and to elucidate the effects of HMG-CoA reductase inhibitors (statins) in Japanese patients with RA. A multicenter observational study was conducted in 488 patients with RA. Serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) levels, and RA activity as assessed by disease activity score 28 (DAS28), and treatment for RA were analyzed retrospectively. In statin-treated patients, drug efficacy was also analyzed. The prevalence of hyper LDL-C, hyper TG, and hypo HDL-C were 29.3, 24.2, and 10.2%, respectively, and the overall prevalence of dyslipidemia was 56.5%. The level of HDL-C was inversely correlated with DAS28. Patients treated with low-dose glucocorticoids showed significantly higher levels of HDL-C and lower TC/HDL-C ratios compared with patients not receiving glucocorticoid treatment. Conversely, patients treated with biologic agents showed significantly higher levels of LDL-C, lower levels of HDL-C, and higher TC/HDL-C ratios. Atorvastatin significantly improved lipid profiles after a few months of treatment. The prevalence of dyslipidemia in Japanese patients with RA is higher than that in the non-RA population. Our result suggests that controlling RA disease activity might improve lipid profiles and eventually lower cardiovascular risk. Low-dose atorvastatin was effective for treatment of dyslipidemia in RA patients but had no apparent effect on RA disease activity.

Molecular analysis of a novel hereditary C3 deficiency with systemic lupus erythematosus.

A case of inherited homozygous complement C3 deficiency (C3D) in a patient with systemic lupus erythematosus (SLE) and the molecular basis for this deficiency are reported. A 22-year-old Japanese male was diagnosed as having SLE and his medical history revealed recurrent tonsillitis and pneumonia. He was diagnosed as having C3D because of undetectable serum C3 level. His parents were consanguineous. Sequence analysis of C3D cDNA revealed a homozygous deletion of exon 39 (84bp). A single base substitution (AG to GG) in the 3'-splice acceptor site of intron 38 was identified by sequencing the genomic DNA. Expression of C3Delta(ex39) cDNA, the C3cDNA lacking exon 39, in COS-7 cells revealed that C3Delta(ex39) was retained in endoplasmic reticulum-Golgi intermediate compartment because of defective secretion. These data indicate that a novel AG-->GG 3'-splice acceptor site mutation in intron 38 caused aberrant splicing of exon 39, resulting in defective secretion of C3.

Novel mutations in TNFRSF1A in patients with typical tumor necrosis factor receptor-associated periodic syndrome and with systemic lupus erythematosus in Japanese.

Molecular defects of TNFRSF1A was investigated in members of a family presenting with typical phenotypes of tumor necrosis factor receptor-associated periodic syndrome (TRAPS) and in patients with the autoimmune disorders, systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Genomic DNA from the members of a family with typical TRAPS, as well as from 100 patients with SLE, 100 patients with RA and 100 healthy individuals, was studied for mutations in exons 2, 3 and 4 of the TNFRSF1A gene. All individuals were Japanese. Three novel missense mutations were identified in the TNFRSF1A. The C70G mutation was identified in family members with typical TRAPS, which was the second case in eastern Asian population. In addition, the T61I and R104Q mutations were each identified in 2 of the 100 SLE patients. The T61I mutation was identified in one of the 100 healthy individuals. No mutations were identified in the 100 RA patients. Functional analysis revealed that PMA-induced shedding of TNFRSF1A from PBMCs was impaired in a patient carrying T61I. A larger scale of study will clarify whether these two mutations, T61I and R104Q, are associated with chronic inflammatory disorders, such as SLE, or not.