Saori Kadowaki

Bio: Saori Kadowaki is an academic researcher from Gifu University. The author has contributed to research in topics: Missense mutation & PSMB9. The author has an hindex of 2, co-authored 9 publications receiving 12 citations.

Heterozygous missense variant of the proteasome subunit β-type 9 causes neonatal-onset autoinflammation and immunodeficiency.

Abstract: Impaired proteasome activity due to genetic variants of certain subunits might lead to proteasome-associated autoinflammatory syndromes (PRAAS). Here we report a de novo heterozygous missense variant of the PSMB9 proteasome subunit gene in two unrelated Japanese infants resulting in amino acid substitution of the glycine (G) by aspartic acid (D) at position 156 of the encoded protein β1i. In addition to PRAAS-like manifestations, these individuals suffer from pulmonary hypertension and immunodeficiency, which are distinct from typical PRAAS symptoms. The missense variant results in impaired immunoproteasome maturation and activity, yet ubiquitin accumulation is hardly detectable in the patients. A mouse model of the heterozygous human genetic variant (Psmb9G156D/+) recapitulates the proteasome defects and the immunodeficiency phenotype of patients. Structurally, PSMB9 G156D interferes with the β-ring-βring interaction of the wild type protein that is necessary for 20S proteasome formation. We propose the term, proteasome-associated autoinflammatory syndrome with immunodeficiency (PRAAS-ID), to indicate a separate category of autoinflammatory diseases, similar to, but distinct from PRAAS, that describes the patients in this study. Genetic variants of proteasome subunit genes have been shown to associate with perturbed immune function. Here authors show that a heterozygous missense variant of the immunoproteasome subunit β-type 9 causes an autoinflammatory/immune deficiency syndrome in humans and in a mouse model.

Prepubertal onset of slipped capital femoral epiphysis associated with hypothyroidism: a case report and literature review.

Abstract: Slipped capital femoral epiphysis (SCFE) is a common hip disorder characterized by displacement of the capital femoral epiphysis from the metaphysic through the femoral epiphyseal plate. SCFE usually occurs during puberty, with obesity a common risk factor. We experienced a rare case of SCFE associated with hypothyroidism in a prepubescent patient who was not obese. The patient was an 8-year-old boy suffering from bilateral SCFE with hypothyroidism. The patient’s growth had started to slow at 4 years of age, and at 8 years he was of short stature. During his evaluation for SCFE management, primary hypothyroidism was diagnosed due to the presence of anti-thyroid peroxidase and anti-thyroglobulin antibodies. After the patient was treated for hypothyroidism, which improved his thyroid function, surgery was performed for bilateral SCFE. Among the 42 patients with SCFE associated with hypothyroidism in the literature, most SCFE occurred during puberty or in adults with delayed epiphyseal closure. Only two patients (4.8%), including the present patient, were ≤9 years old. Although being overweight or obese is common for patients with SCFE associated with hypothyroidism (76.0%), it was not observed in the present case. Persistent hypothyroidism, however, may be a risk factor for SCFE even before puberty and without obesity.

Functional analysis of novel A20 variants in patients with atypical inflammatory diseases.

Abstract: A20 haploinsufficiency (HA20) is an early-onset autoinflammatory disease caused by mutations in the TNFAIP3 gene, which encodes the protein A20. Numerous truncating mutations in the TNFAIP3 gene have been reported in HA20 patients, whereas fewer missense variants have had their pathogenicity confirmed. Here, we evaluated the pathogenic significance of three previously unreported missense variants of the TNFAIP3 gene in suspected cases of HA20. We obtained the clinical features and immunological data of three patients with missense variants (Glu192Lys, Ile310Thr, and Gln709Arg) of unknown significance of TNFAIP3. We then performed in vitro functional assays including analysis of nuclear factor (NF)-κB reporter gene activity, detection of A20 expression and phosphorylation of A20 by IκB kinase β (IKKβ), and K63-deubiquitination assay using TNFAIP3-deficient HEK293 cells. Three known pathogenic missense mutations reported previously were also investigated. The inhibitory effect on NF-κB reporter gene activity was significantly disrupted by A20 Glu192Lys and the three known mutations. The variants Ile310Thr and Gln709Arg did not show a difference from the wild type in any of the assays performed in this study. Among the three variants in the TNFAIP3 gene, Glu192Lys was interpreted as being likely pathogenic, but Ile310Thr and Gln709Arg as being not pathogenic (uncertain significance and likely benign, respectively), based on the American College of Medical Genetics and Genomics standards and guidelines. Our study highlights the necessity of performing in vitro functional assays, notably, NF-κB reporter gene assay, to evaluate the pathogenicity of TNFAIP3 missense variants for the accurate diagnosis of HA20.

A pediatric case of food-dependent exercise-induced anaphylaxis due to rice bran

Abstract: Food-dependent exercise-induced anaphylaxis (FDEIA) caused by fruits and vegetables is increasing in recent years, but rice-induced FDEIA is rarely reported. The mechanism of FDEIA is unclear, although percutaneous sensitization occurs in some cases. A 14-year-old adolescent came our hospital who had 6 episodes of unknown FDEIA occurring from age 13. He affected atopic dermatitis in infancy, and he had been polishing rice daily to help with housework, and also had occasionally begun to observe urticaria while bathing after eating rice from 5 years old. Antigen-specific immunoglobulin E antibody titers (ImmunoCAP) were 1.35 UAmL for rice, 23.6 UAmL for orchard grass. Oral food challenge and exercise provocation test with polished rice were negative. An oral food challenge with rice bran was also negative, but exercise provocation test induced severe anaphylaxis. IgE immunoblotting with rice bran detected patient-specific bands, as 25-, 35-, 50-, and 60 kDa, and the 25- and 60-kDa bands were heat-resistant. In a suppression test using rice bran, these bands disappeared or diminished. In an inhibition test against orchard grass pollen with rice bran, inhibition was not observed. Conversely, an inhibition test against rice bran with orchard grass pollen, inhibition was observed in a concentration-dependent manner. This is extremely rare case of FDEIA in children, caused by rice bran. Furthermore, it might be induced by percutaneous sensitization. In FDEIA, it is necessary to scrutinize the possibility that rice bran may be the cause even in children.

Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee

Abstract: We report the updated classification of inborn errors of immunity, compiled by the International Union of Immunological Societies Expert Committee. This report documents the key clinical and laboratory features of 55 novel monogenic gene defects, and 1 phenocopy due to autoantibodies, that have either been discovered since the previous update (published January 2020) or were characterized earlier but have since been confirmed or expanded in subsequent studies. While variants in additional genes associated with immune diseases have been reported in the literature, this update includes only those that the committee assessed that reached the necessary threshold to represent novel inborn errors of immunity. There are now a total of 485 inborn errors of immunity. These advances in discovering the genetic causes of human immune diseases continue to significantly further our understanding of molecular, cellular, and immunological mechanisms of disease pathogenesis, thereby simultaneously enhancing immunological knowledge and improving patient diagnosis and management. This report is designed to serve as a resource for immunologists and geneticists pursuing the molecular diagnosis of individuals with heritable immunological disorders and for the scientific dissection of cellular and molecular mechanisms underlying monogenic and related human immune diseases.

Trichophyton indotineae sp. nov.: A New Highly Terbinafine-Resistant Anthropophilic Dermatophyte Species

Abstract: In this report, we describe the first isolation of two highly terbinafine (TRF)-resistant Trichophyton interdigitale-like strains from a Nepali patient and an Indian patient with tinea corporis in Japan. These strains (designated NUBS19006 and NUBS19007) exhibited a TRF minimal inhibitory concentration (MIC) of > 32 mg/L and contained a missense mutation (Phe397Leu) in squalene epoxidase (SQLE) gene. The internal transcribed spacer (ITS) region sequences amplified from the isolates (NUBS19006 and NUBS19007) were 99.5% identical to Japanese isolates of T. interdigitale and T. interdigitale strain CBS 428.63. The homology of region sequences were also 97.6% identical to T. mentagrophytes strain CBS 318.56. Moreover, the ITS sequences amplified from the isolates were 100% identical to highly TRF-resistant strains of T. interdigitale, which were isolated in Delhi, India, and harbored mutations in SQLE. The urease test on Christensen’s urease agar was positive for T. mentagrophytes and T. interdigitale after 7 days of incubation. On the other hand, the type strain of T. rubrum CBS 100081 T and highly TRF-resistant strains (NUBS19006 and NUBS19007) were negative on Christensen urease agar after 7 and 14 days of incubation. Moreover, NUBS19006 and NUBS19007 were also negative reaction on the hair perforation test. To avoid confusion in the taxonomy of the T. mentagrophytes/T. interdigitale complex, we suggest that the highly TRF-resistant Indian strains be considered a new species independent of T. interdigitale, according to clinical and mycological features.

T Follicular Helper Cell Differentiation

Abstract: When B cells respond to an infection, they often require help from CD4 + T cells to mount a proper response. It is thought that a subset of CD4 + effector T cells, called T follicular helper cells (T FH ), performs this function. Several subsets of effector CD4 + T cells arise, depending on the type of infection, which have distinct transcriptional programs driving their differentiation. Whether this is also the case for T FH cells has not been clear (see the Perspective by Awasthi and Kuchroo). Nurieva et al. and Johnston et al. now demonstrate that the transcription factor Bcl6 is both necessary and sufficient for T FH differentiation and subsequent B cell–mediated immunity, suggesting that it is a master regulator of this lineage. Johnston et al. also show that expression of Bcl6 and the transcription factor Blimp-1 is reciprocally regulated in T FH cells and that, when ectopically expressed, Blimp-1 inhibits T FH development. R. I. Nurieva, Y. Chung, G. J. Martinez, X. O. Yang, S. Tanaka, T. D. Matskevitch, Y.-H. Wang, C. Dong, Bcl6 mediates the development of T follicular helper cells. Science 325 , 1001–1005 (2009). [Abstract][Full Text] R. J. Johnston, A. C. Poholek, D. DiToro, I. Yusuf, D. Eto, B. Barnett, A. L. Dent, J. Craft, S. Crotty, Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science 325 , 1006–1010 (2009). [Abstract][Full Text] A. Awasthi, V. K. Kuchroo, The yin and yang of follicular helper T cells. Science 325 , 953–955 (2009). [Summary][Full Text]