Publications by authors named "Kazuyoshi Hosomichi"

100 Publications

Predictors associated with a better response to the Japanese aluminum-free hepatitis A vaccine, Aimmugen , for people living with HIV.

Hepatol Res 2021 Nov 26. Epub 2021 Nov 26.

Division of Infectious Diseases, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

Aim: After the hepatitis A virus (HAV) outbreak among men who have sex with men (MSM) around 2018, the importance of HAV vaccination was emphasized, especially for MSM-living with human immunodeficiency virus (MSM-LWHIV). Aimmugen is licensed and distributed exclusively in Japan. While administration of three doses is recommended, 85% of recipients in the general population were reported to acquire seroprotection after the second dose. In this study, we evaluated the efficacy of two or three vaccine doses along with predictors associated with the response to Aimmugen in MSM-LWHIV.

Methods: We retrospectively examined anti-HA-IgG titers of MSM-LWHIV vaccinated with Aimmugen in our hospital. Patients' data were collected from medical records.

Results: Between January 2018 and October 2019, 141 subjects whose median age was 46 years old, were examined. All the subjects were on antiretroviral therapy (ART) and the median CD4 count was 615/μL. The acquisition rate of protectable anti-HA-IgG titers after the second and third dose was 71.1% and 98.6%, respectively. In 114 subjects whose anti-HA-IgG titers were tested after the second-dose, factors significantly associated with better response were prolonged ART duration and higher CD4 count. The titers of anti-HA-IgG after the third dose were higher in those who became seropositive after the second-dose than those who did not.

Conclusions: Three-dose of Aimmugen for MSM-LWHIV was effective while two-dose was less effective compared to non-HIV-infected people. People-LWHIV with shorter duration of ART and lesser CD4 cell count achieved lower titers of anti-HA-IgG and might require an additional vaccination. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/hepr.13736DOI Listing
November 2021

Glucokinase-maturity onset diabetes mellitus in the young suggested by factory-calibrated glucose monitoring data: a case report.

Endocr J 2021 Nov 19. Epub 2021 Nov 19.

Department of Diabetes, Endocrinology and Metabolism/Department of Rheumatology and Clinical Immunology, Gifu University Graduate School of Medicine, Gifu, Japan.

Glucokinase has an important role in regulating glycolysis as a glucose sensor in liver and pancreatic β cells. Glucokinase-maturity onset diabetes in young (GCK-MODY also known as MODY2) is caused by autosomal dominant gene mutation of the GCK gene; it is characterized by mild fasting hyperglycemia and small 2-h glucose increment during 75 g-oral glucose tolerance test (OGTT) as well as near-normal postprandial glucose variabilities. A 10-year-old girl with family history of diabetes visited her physician after being found positive for urinary glucose by school medical checkup. She received a diagnosis of diabetes based on the laboratory data: 75 g-OGTT (mild fasting hyperglycemia and small 2-h glucose increment) and factory-calibrated glucose monitoring (mild elevation of average glucose level and near-normal glycemic variability), which raised suspicion of GCK-MODY. She was then referred to our institution for genetic examination, which revealed a GCK heterozygous mutation (NM_000162: exon10: c.1324G>T: p.E442X) in the proband as well as in her mother and maternal grandmother, who had been receiving anti-diabetes medications without knowing that they had GCK-MODY specifically. GCK-MODY cases show incidence of microvascular and macrovascular diseases similar to that of normal subjects, and their glucose levels are adequately controlled without anti-diabetes drug use. Thus, early and definitive diagnosis of MODY2 by genetic testing is important to avoid unnecessary medication.
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http://dx.doi.org/10.1507/endocrj.EJ21-0526DOI Listing
November 2021

Effects of functional variants of vitamin C transporter genes on apolipoprotein E E4-associated risk of cognitive decline: The Nakajima study.

PLoS One 2021 15;16(11):e0259663. Epub 2021 Nov 15.

Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.

Apolipoprotein E E4 (APOE4) is a risk factor for cognitive decline. A high blood vitamin C (VC) level reduces APOE4-associated risk of developing cognitive decline in women. In the present study, we aimed to examine the effects of functional variants of VC transporter genes expressed in the brain (SLC2A1, SLC2A3, and SLC23A2) on APOE4-associated risk of developing cognitive decline. This case-control study involved 393 Japanese subjects: 252 cognitively normal and 141 cognitively impaired individuals (87 mild cognitive impairment and 54 dementia). Database searches revealed that rs1279683 of SLC23A2, and rs710218 and rs841851 of SLC2A1 are functional variants that are significantly associated with the altered expression of the respective genes and genotyped as three single nucleotide variants (SNVs). When stratified by SNV genotype, we found a significant association between APOE4 and cognitive decline in minor allele carriers of rs1279683 (odds ratio [OR] 2.02, 95% CI, 1.05-3.87, p = 0.035) but not in the homozygote carriers of the major allele. Significant associations between APOE4 and cognitive decline were also observed in participants with major allele homozygotes of rs710218 (OR 2.35, 95% CI, 1.05-5.23, p = 0.037) and rs841851 (OR 3.2, 95% CI, 1.58-6.46, p = 0.0012), but not in minor allele carriers of the respective SNVs. In contrast, the three functional SNVs showed no significant effect on cognitive decline. Our results imply that functional SNVs of VC transporter genes can affect APOE4-associated risk of developing cognitive decline via altered VC levels in the brain.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0259663PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8592483PMC
November 2021

Allelic and haplotypic HLA diversity in indigenous Malaysian populations explored using Next Generation Sequencing.

Hum Immunol 2021 Oct 4. Epub 2021 Oct 4.

Human Genetics Laboratory, Department of Genomics and Evolutionary Biology, National Institute of Genetics, Mishima, Japan.

The heterogenous population of Malaysia includes more than 50 indigenous groups, and characterizing their HLA diversity would not only provide insights to their ancestry, but also on the effects of natural selection on their genome. We utilized hybridization-based sequence capture and short-read sequencing on the HLA region of 172 individuals representing seven indigenous groups in Malaysia (Jehai, Kintaq, Temiar, Mah Meri, Seletar, Temuan, Bidayuh). Allele and haplotype frequencies of HLA-A, -B, -C, -DRB1, -DQA1, -DQB1, -DPA1, and -DPB1 revealed several ancestry-informative markers. Using SNP-based heterozygosity and pairwise Fst, we observed signals of natural selection, particularly in HLA-A, -C and -DPB1 genes. Consequently, we showed the impact of natural selection on phylogenetic inference using HLA and non-HLA SNPs. We demonstrate the utility of Next Generation Sequencing for generating unambiguous, high-throughput, high-resolution HLA data that adds to our knowledge of HLA diversity and natural selection in indigenous minority groups.
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http://dx.doi.org/10.1016/j.humimm.2021.09.005DOI Listing
October 2021

Somatic mutations in oral squamous cell carcinomas in 98 Japanese patients and their clinical implications.

Cancer Treat Res Commun 2021 Sep 17;29:100456. Epub 2021 Sep 17.

Department of Oral and Maxillofacial Surgery, Tokai University School of Medicine,143 Shimokasuya, Isehara, Kanagawa, Japan. Electronic address:

Introduction: The somatic mutational profile of oral squamous cell carcinoma (OSCC) among Japanese patients has been less investigated, partly because of the rarity of the tumor. Moreover, previous studies have either used formalin-fixed paraffin-embedded samples or lacked paired normal tissues. We aimed to determine somatic mutations in the exomes of 76 genes, including 50 driver genes of solid cancers and NOTCH-related genes, some of which are previously reported as frequently mutated in head and neck squamous cell carcinoma or OSCC.

Materials And Methods: We used fresh-frozen tumor/normal-paired samples from 98 treatment-naïve Japanese patients with OSCC and analyzed their correlations with clinicopathological characteristics and survival.

Results: We identified 136 exonic mutations, including 78 non-synonymous mutations, 13 synonymous mutations, 22 nonsense mutations, 2 non-frameshift deletions, 11 frameshift deletion, and 5 each of splice-site and frameshift insertions. The most frequently mutated genes were TP53 (36.7%), FAT1 (9.2%), NOTCH1 (8.2%), CDKN2A (7.1%), ZFHX4 (5.1%), CASP8 (4.1%), EP300 (4.1%), and KMT2D (4.1%). We followed up 90 of the 98 patients for 3 years. Among them, TP53 mutation was associated with significantly shorter 3-year disease-free survival. Most of the identified TP53 mutations occurred in the DNA-binding domain and were functionally deleterious.

Discussion: Our findings and the mutation spectra can contribute to the development of a therapeutic strategy for Japanese patients with OSCC.
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http://dx.doi.org/10.1016/j.ctarc.2021.100456DOI Listing
September 2021

Whole-Genome Sequencing of a 900-Year-Old Human Skeleton Supports Two Past Migration Events from the Russian Far East to Northern Japan.

Genome Biol Evol 2021 Sep;13(9)

Department of Human Biology and Anatomy, Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan.

Recent studies on paleogenomics have reported some Paleolithic and Neolithic genomes that have provided new insights into the human population history in East and Northeast Asia. However, there remain some cases where more recent migration events need to be examined to elucidate the detailed formation process of local populations. Although the area around northern Japan is one of the regions archaeologically suggested to have been affected by migration waves after the Neolithic period, the genetic source of these migrations are still unclear. Thus, genomic data from such past migrant populations would be highly informative to clarify the detailed formation process of local populations in this region. Here, we report the genome sequence of a 900-year-old adult female (NAT002) belonging to the prehistoric Okhotsk people, who have been considered to be the past migrants to northern Japan after the Neolithic period. We found a close relationship between NAT002 and modern Lower Amur populations and past admixture events between the Amur, Jomon, and Kamchatka ancestries. The admixture dating suggested migration of Amur-related ancestry at approximately 1,600 BP, which is compatible with the archaeological evidence regarding the settlement of the Okhotsk people. Our results also imply migration of Kamchatka-related ancestry at approximately 2,000 BP. In addition, human leukocyte antigen (HLA) typing detected the HLA-B*40 allele, which is reported to increase the risk of arthritis, suggesting the genetic vulnerability of NAT002 to hyperostosis, which was observed around her chest clavicle.
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http://dx.doi.org/10.1093/gbe/evab192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8449830PMC
September 2021

The limits of clinical findings in similar phenotypes, from Carpenter to ATRX syndrome using a whole exome sequencing approach: a case review.

Hum Genomics 2021 08 4;15(1):49. Epub 2021 Aug 4.

School of Medicine, Universidad San Francisco de Quito, Quito, Ecuador.

Background: The diagnostic process for uncommon disorders with similar manifestations is complicated and requires newer technology, like gene sequencing for a correct diagnosis.

Main Body: We described two brothers clinically diagnosed with Carpenter syndrome, which is a condition characterized by the premature fusion of certain skull bones (craniosynostosis), abnormalities of the fingers and toes, and other developmental problems, for which they underwent craniotomies. However, whole exome sequencing analysis concluded a novel pathological variation in the ATRX chromatin remodeler gene and protein remodeling demonstrated structural variations that decreased the function, giving a completely different diagnosis to these patients.

Conclusion: Our study focuses on the importance of using newer technologies, such as whole exome sequencing analysis, in patients with ambiguous phenotypes.
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http://dx.doi.org/10.1186/s40246-021-00348-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8336023PMC
August 2021

Relationships among the β3-adrenargic receptor gene Trp64Arg polymorphism, hypertension, and insulin resistance in a Japanese population.

PLoS One 2021 4;16(8):e0255444. Epub 2021 Aug 4.

Department of Environmental and Preventive Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.

A polymorphism in the ADRB3 gene (Trp64Arg) has been associated with obesity, insulin resistance, and hypertension. This cross-sectional study investigated the relationships among this polymorphism, hypertension, and insulin resistance values (HOMA-IR) in 719 Japanese subjects aged 40 years and older. The genotype frequencies of Trp64Trp (homozygous, wild), Trp64Arg (heterozygous, variant), and Arg64Arg (homozygous, variant) were 466 (65%), 233 (32%), and 20 (3%), respectively. Insulin resistance was associated with an increased risk of hypertension in a Japanese population. This relationship was dependent on the presence or absence of the Trp64Arg polymorphism (odds ratio, 2.054; confidence interval, 1.191 to 3.541; P value, 0.010). Therefore, the Trp64Arg polymorphism of ADRB3 was associated with hypertension and insulin resistance in a healthy Japanese population. This relationship, which was dependent on the polymorphism, may predict the development of hypertension and diabetes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0255444PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8336805PMC
November 2021

Dysbiotic gut microbiota in pancreatic cancer patients form correlation networks with the oral microbiota and prognostic factors.

Am J Cancer Res 2021 15;11(6):3163-3175. Epub 2021 Jun 15.

Department of Gastroenterology, Graduate School of Medical Sciences, Kanazawa University 13-1 Takara-Machi, Kanazawa, Ishikawa, Japan.

Microbiota in the gut and oral cavities of pancreatic cancer (PC) patients differ from those of healthy persons, and bacteria in PC tissues are associated with patients' prognoses. However, the species-level relationship between a dysbiotic gut, oral and cancerous microbiota, and prognostic factors remains unknown. Whole-genome sequencing was performed with fecal DNA from 24 PC patients and 18 healthy persons (HD). Microbial taxonomies, metabolic pathways, and viral presence were determined. DNA was sequenced from saliva and PC tissues, and the association between the gut, oral, and cancer microbiota and prognostic factors in PC patients was analyzed. The PC microbiota were altered from those of the healthy microbiota in terms of microbial taxonomy, pathways and viral presence. Twenty-six species differed significantly between the PC and HD microbiota. Six fecal microbes, including , were associated with an increased hazard of death. In the co-occurrence network, microbes that were abundant in PC patients were plotted close together and formed clusters with prognosis-associated microbes, including . Multiple salivary microbes were present in the co-occurrence network. and were detected in the PC tissues and formed a network with the fecal and salivary microbes. The dysbiotic gut microbiota in the PC patients formed a complex network with the oral and cancerous microbiota, and gut microbes abundant in the PC patients were closely linked with poor prognostic factors in the network.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263681PMC
June 2021

The ATF6β-calreticulin axis promotes neuronal survival under endoplasmic reticulum stress and excitotoxicity.

Sci Rep 2021 06 22;11(1):13086. Epub 2021 Jun 22.

Department of Neuroanatomy, Graduate School of Medical Sciences, Kanazawa University, 13-1 Takara-Machi, Kanazawa City, Ishikawa, 920-8640, Japan.

While ATF6α plays a central role in the endoplasmic reticulum (ER) stress response, the function of its paralogue ATF6β remains elusive, especially in the central nervous system (CNS). Here, we demonstrate that ATF6β is highly expressed in the hippocampus of the brain, and specifically regulates the expression of calreticulin (CRT), a molecular chaperone in the ER with a high Ca-binding capacity. CRT expression was reduced to ~ 50% in the CNS of Atf6b mice under both normal and ER stress conditions. Analysis using cultured hippocampal neurons revealed that ATF6β deficiency reduced Ca stores in the ER and enhanced ER stress-induced death. The higher levels of death in Atf6b neurons were recovered by ATF6β and CRT overexpressions, or by treatment with Ca-modulating reagents such as BAPTA-AM and 2-APB, and with an ER stress inhibitor salubrinal. In vivo, kainate-induced neuronal death was enhanced in the hippocampi of Atf6b and Calr mice, and restored by administration of 2-APB and salubrinal. These results suggest that the ATF6β-CRT axis promotes neuronal survival under ER stress and excitotoxity by improving intracellular Ca homeostasis.
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http://dx.doi.org/10.1038/s41598-021-92529-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8219835PMC
June 2021

Polygenic risk scores for low-density lipoprotein cholesterol and familial hypercholesterolemia.

J Hum Genet 2021 Nov 10;66(11):1079-1087. Epub 2021 May 10.

Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.

Familial hypercholesterolemia (FH) is an autosomal dominant monogenic disorder characterized by elevated levels of low-density lipoprotein cholesterol (LDL-C) and an increased risk of premature coronary artery disease (CAD). Recently, it has been shown that a high polygenic risk score (PRS) could be an independent risk factor for CAD in FH patients of European ancestry. However, it is uncertain whether PRS is also useful for risk stratification of FH patients in East Asia. We recruited and genotyped clinically diagnosed FH (CDFH) patients from the Kanazawa University Mendelian Disease FH registry and controls from the Shikamachi Health Improvement Practice genome cohort in Japan. We calculated PRS from 3.6 million variants of each participant (imputed from the 1000 Genome phase 3 Asian dataset) for LDL-C (PRS) using a genome-wide association study summary statistic from the BioBank Japan Project. We assessed the association of PRS with LDL-C and CAD among and within monogenic FH, mutation negative CDFH, and controls. We tested a total of 1223 participants (376 FH patients, including 173 with monogenic FH and 203 with mutation negative CDFH, and 847 controls) for the analyses. PRS was significantly higher in mutation negative CDFH patients than in controls (p = 3.1 × 10). PRS was also significantly linked to LDL-C in controls (p trend = 3.6 × 10) but not in FH patients. Moreover, we could not detect any association between PRS and CAD in any of the groups. In conclusion, mutation negative CDFH patients demonstrated significantly higher PRS than controls. However, PRS may have little additional effect on LDL-C and CAD among FH patients.
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http://dx.doi.org/10.1038/s10038-021-00929-7DOI Listing
November 2021

Identification of candidate PAX2-regulated genes implicated in human kidney development.

Sci Rep 2021 04 27;11(1):9123. Epub 2021 Apr 27.

Department of Nephrology and Laboratory Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8640, Japan.

PAX2 is a transcription factor essential for kidney development and the main causative gene for renal coloboma syndrome (RCS). The mechanisms of PAX2 action during kidney development have been evaluated in mice but not in humans. This is a critical gap in knowledge since important differences have been reported in kidney development in the two species. In the present study, we hypothesized that key human PAX2-dependent kidney development genes are differentially expressed in nephron progenitor cells from induced pluripotent stem cells (iPSCs) in patients with RCS relative to healthy individuals. Cap analysis of gene expression revealed 189 candidate promoters and 71 candidate enhancers that were differentially activated by PAX2 in this system in three patients with RCS with PAX2 mutations. By comparing this list with the list of candidate Pax2-regulated mouse kidney development genes obtained from the Functional Annotation of the Mouse/Mammalian (FANTOM) database, we prioritized 17 genes. Furthermore, we ranked three genes-PBX1, POSTN, and ITGA9-as the top candidates based on closely aligned expression kinetics with PAX2 in the iPSC culture system and susceptibility to suppression by a Pax2 inhibitor in cultured mouse embryonic kidney explants. Identification of these genes may provide important information to clarify the pathogenesis of RCS, human kidney development, and kidney regeneration.
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http://dx.doi.org/10.1038/s41598-021-88743-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079710PMC
April 2021

Molecular features of tumor-derived genetic alterations in circulating cell-free DNA in virtue of autopsy analysis.

Sci Rep 2021 04 16;11(1):8398. Epub 2021 Apr 16.

Respiratory Medicine, Kanazawa University Hospital, Kanazawa, Japan.

In cancer patients, circulating cell-free DNA (cfDNA) includes tumor-derived DNA (tDNA). cfDNA has been used clinically for non-invasive gene mutation testing. The aim of this study was to characterize the features of the genetic alterations detected in cfDNA. This study included 6 patients with primary lung cancer who died due to cancer progression. Tumors were biopsied at autopsy. Genetic alteration profiles were obtained using next generation sequencing. The features of the tDNA genetic alterations detected in cfDNA included a higher frequency of being present in multiple tumors (67% truncal mutations, 36% shared mutations, and 4% individual mutations) and a higher variant allele frequency (VAF; 47.6% versus 4.1% for tDNA alterations detected in cfDNA versus not detected in cfDNA, respectively). The data revealed that the tumor-derived genetic alterations most easily detected in cfDNA were truncal mutations with a high VAF. These results showed that essential genetic alterations enriched in cfDNA could help to characterize cancer cells and that genetic testing using cfDNA has advantages in the detection of fundamental regulatory aberrations occurring during tumorigenesis.
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http://dx.doi.org/10.1038/s41598-021-87094-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052353PMC
April 2021

Analysis of HLA gene polymorphisms in East Africans reveals evidence of gene flow in two Semitic populations from Sudan.

Eur J Hum Genet 2021 Aug 22;29(8):1259-1271. Epub 2021 Mar 22.

Human Genetics Laboratory, Department of Genomics and Evolutionary Biology, National Institute of Genetics, Mishima, Shizuoka, Japan.

Sudan, a northeastern African country, is characterized by high levels of cultural, linguistic, and genetic diversity, which is believed to be affected by continuous migration from neighboring countries. Consistent with such demographic effect, genome-wide SNP data revealed a shared ancestral component among Sudanese Afro-Asiatic speaking groups and non-African populations, mainly from West Asia. Although this component is shared among all Afro-Asiatic speaking groups, the extent of this sharing in Semitic groups, such as Sudanese Arab, is still unknown. Using genotypes of six polymorphic human leukocyte antigen (HLA) genes (i.e., HLA-A, -C, -B, -DRB1, -DQB1, and -DPB1), we examined the genetic structure of eight East African ethnic groups with origins in Sudan, South Sudan, and Ethiopia. We identified informative HLA alleles using principal component analysis, which revealed that the two Semitic groups (Gaalien and Shokrya) constituted a distinct cluster from the other Afro-Asiatic speaking groups in this study. The HLA alleles that distinguished Semitic Arabs co-exist in the same extended HLA haplotype, and those alleles are in strong linkage disequilibrium. Interestingly, we find the four-locus haplotype "C*12:02-B*52:01-DRB1*15:02-DQB1*06:01" exclusively in non-African populations and it is widely spread across Asia. The identification of this haplotype suggests a gene flow from Asia, and likely these haplotypes were brought to Africa through back migration from the Near East. These findings will be of interest to biomedical and anthropological studies that examine the demographic history of northeast Africa.
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http://dx.doi.org/10.1038/s41431-021-00845-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8384866PMC
August 2021

A novel RFX6 heterozygous mutation (p.R652X) in maturity-onset diabetes mellitus: A case report.

J Diabetes Investig 2021 Oct 9;12(10):1914-1918. Epub 2021 Apr 9.

Department of Diabetes and Endocrinology, Gifu University Graduate School of Medicine, Gifu, Japan.

Heterozygous RFX6 mutation has emerged as a potential cause of maturity-onset diabetes mellitus of the young (MODY). A 16-year-old female was diagnosed with diabetes by her family doctor and was referred to our institution for genetic examination. Genetic testing revealed a novel RFX6 heterozygous mutation (NM_173560: exon17: c.1954C>T: p.R652X) in the patient and in her mother and brother. She had no islet-specific autoantibodies and showed a reduced meal-induced response of insulin, glucose-dependent insulinotropic polypeptide, and glucagon-like peptide-1, which is consistent with the phenotype of MODY due to heterozygous RFX6 mutation. In conclusion, we report a case of MODY due to a novel heterozygous mutation, p.R652X.
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http://dx.doi.org/10.1111/jdi.13545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8504905PMC
October 2021

Characterization of LILRB3 and LILRA6 allelic variants in the Japanese population.

J Hum Genet 2021 Jul 1;66(7):739-748. Epub 2021 Feb 1.

Advanced Preventive Medical Sciences Research Center, Kanazawa University, Ishikawa, Japan.

Leukocyte immunoglobulin (Ig)-like receptors (LILRs) are encoded by members of a human multigene family, comprising 11 protein-coding genes and two pseudogenes. Among the LILRs, LILRB3 and LILRA6 show the highest homology with each other, along with high allelic and copy number variations. Therefore, it has been difficult to discriminate between them, both genetically and functionally, precluding disease association studies of LILRB3 and LILRA6. In this study, we carefully performed variant screening of LILRB3 and LILRA6 by cDNA cloning from Japanese individuals and identified four allelic lineages showing significantly high non-synonymous-to-synonymous ratios in pairwise comparisons. Furthermore, the extracellular domains of the LILRB3*JP6 and LILRA6*JP1 alleles were identical at the DNA level, suggesting that gene conversion-like events diversified LILRB3 and LILRA6. To determine the four allelic lineages from genomic DNA, we established a lineage typing method that accurately estimated the four allelic lineages in addition to specific common alleles from genomic DNA. Analysis of LILRA6 copy number variation revealed one, two, and three copies of LILRA6 in the Japanese-in-Tokyo (JPT) population. Flow cytometric analysis showed that an anti-LILRB3 antibody did not recognize the second most common lineage in the Japanese population, indicating significant amino acid differences across the allelic lineages. Taken together, our findings indicate that our lineage typing is useful for classifying the lineage-specific functions of LILRB3 and LILRA6, serving as the basis for disease association studies.
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http://dx.doi.org/10.1038/s10038-021-00906-0DOI Listing
July 2021

MCPIP1 reduces HBV-RNA by targeting its epsilon structure.

Sci Rep 2020 11 27;10(1):20763. Epub 2020 Nov 27.

Department of Molecular Genetics, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, 920-8640, Japan.

Hepatitis B virus (HBV) is the major causative factor of chronic viral hepatitis, liver cirrhosis, and hepatocellular carcinoma. We previously demonstrated that a proinflammatory cytokine IL-1β reduced the level of HBV RNA. However, the mechanism underlying IL-1β-mediated viral RNA reduction remains incompletely understood. In this study, we report that immune regulator Monocyte chemotactic protein-1-induced protein 1 (MCPIP1) can reduce HBV RNA in hepatocytes. MCPIP1 expression level was higher in the liver tissue of HBV-infected patients and mice. Overexpression of MCPIP1 decreased HBV RNA, whereas ablating MCPIP1 in vitro enhanced HBV production. The domains responsible for RNase activity or oligomerization, were required for MCPIP1-mediated viral RNA reduction. The epsilon structure of HBV RNA was important for its antiviral activity and cleaved by MCPIP1 in the cell-free system. Lastly, knocking out MCPIP1 attenuated the anti-HBV effect of IL-1β, suggesting that MCPIP1 is required for IL-1β-mediated HBV RNA reduction. Overall, these results suggest that MCPIP1 may be involved in the antiviral effect downstream of IL-1β.
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http://dx.doi.org/10.1038/s41598-020-77166-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699622PMC
November 2020

HLA-B*39:01:01 is a novel risk factor for antithyroid drug-induced agranulocytosis in Japanese population.

Pharmacogenomics J 2021 02 22;21(1):94-101. Epub 2020 Sep 22.

Human Genetics Laboratory, National Institute of Genetics, Mishima, Japan.

Antithyroid drug (ATD) is a mainstay of Graves' disease (GD). About 0.1-0.5% of patients with GD treated with ATD exhibit ATD-induced agranulocytosis, which is characterized by severe reduction of circulating neutrophils. Immune-mediated responses have been proposed as a possible mechanism for the pathogenesis of ATD-induced agranulocytosis. Although it has been reported that the HLA class II allele (HLA-DRB1*08:03) was associated with ATD-induced agranulocytosis in multiple populations, the entire HLA region have not been explored in Japanese. Therefore, we performed HLA sequencing for 10 class I and 11 class II genes in 87 patients with ATD-induced agranulocytosis and 384 patients with GD who did not show ATD-induced agranulocytosis. By conducting case-control association studies at the HLA allele and haplotype levels, we replicated the association between HLA-DRB1*08:03:02 and ATD-induced agranulocytosis (P = 5.2 × 10, odds ratio = 2.80), and identified HLA-B*39:01:01 as an independent risk factor (P = 1.4 × 10, odds ratio = 3.35). To verify reproducibility of the novel association of HLA-B*39:01:01, we reanalyzed allele frequency data for HLA-B*39:01:01 from previous case-control association studies. The association of HLA-B*39:01:01 was significantly replicated in Chinese (P = 9.0 × 10), Taiwanese (P = 1.1 × 10), and European populations (P = 5.2 × 10). A meta-analysis combining results from the previous and current studies reinforced evidence of the association between HLA-B*39:01:01 and ATD-induced agranulocytosis (P = 1.2 × 10, pooled OR = 3.66, 95% CI; 2.41-5.57). The results of this study will provide a better understanding of the pathogenesis of ATD-induced agranulocytosis in the context of HLA-mediated hypersensitivity reactions.
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http://dx.doi.org/10.1038/s41397-020-00187-4DOI Listing
February 2021

Alopecia areata susceptibility variant in MHC region impacts expressions of genes contributing to hair keratinization and is involved in hair loss.

EBioMedicine 2020 Jul 21;57:102810. Epub 2020 Jun 21.

Department of Dermatology and Allergology, and Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo, Tokyo 113-8421, Japan. Electronic address:

Background: Alopecia areata (AA) is considered a highly heritable, T-cell-mediated autoimmune disease of the hair follicle. However, no convincing susceptibility gene has yet been pinpointed in the major histocompatibility complex (MHC), a genome region known to be associated with AA as compared to other regions.

Methods: We engineered mice carrying AA risk allele identified by haplotype sequencing for the MHC region using allele-specific genome editing with the CRISPR/Cas9 system. Finally, we performed functional evaluations in the mice and AA patients with and without the risk allele.

Findings: We identified a variant (rs142986308, p.Arg587Trp) in the coiled-coil alpha-helical rod protein 1 (CCHCR1) gene as the only non-synonymous variant in the AA risk haplotype. Furthermore, mice engineered to carry the risk allele displayed a hair loss phenotype. Transcriptomics further identified CCHCR1 as a novel component interacting with hair cortex keratin in hair shafts. Both, these alopecic mice and AA patients with the risk allele displayed morphologically impaired hair and comparable differential expression of hair-related genes, including hair keratin and keratin-associated proteins (KRTAPs).

Interpretation: Our results implicate CCHCR1 with the risk allele in a previously unidentified subtype of AA based on aberrant keratinization in addition to autoimmune events.

Funding: This work was supported by JSPS KAKENHI (JP16K10177) and the NIHR UCLH Biomedical Research center (BRC84/CN/SB/5984).
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http://dx.doi.org/10.1016/j.ebiom.2020.102810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317227PMC
July 2020

A case of MODY5-like manifestations without mutations or deletions in coding and minimal promoter regions of the HNF1B gene.

Endocr J 2020 Sep 27;67(9):981-988. Epub 2020 May 27.

Department of Diabetes and Endocrinology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan.

Pancreatic tail hypoplasia is a common manifestation of maturity onset diabetes of the young (MODY) 5 that can cause reno-genito-urinary malformations such as renal cysts and bicornuate uterus. A 69-year-old female was admitted to our hospital for consultation on her relatively high HbA1c value. At age 20, she was diagnosed with uterus bicornis. At age 68, she was diagnosed with pancreas tail hypoplasia, renal cysts and non-functioning pancreatic neuroendocrine tumor (NET) in addition to right hydronephrosis due to multiple ureteral bladder carcinomas. She received total right nephrectomy, ureterectomy and partial cystectomy for multiple ureteral bladder carcinomas [non-invasive papillary urothelial carcinoma, low grade (G1), pTa, LV10, u-rtx, RM0, and pN0 (0/8)]. She also received distal pancreatomy for pancreatic NET [NET G1]. She then was referred to our department at age 69 due to increase in her HbA1c value from 6.2 to 7.2%; 75 g oral glucose tolerance test revealed impaired glucose tolerance. Her clinical characteristics (uterus bicornis, pancreas hypoplasia, and renal cysts) closely resembled the phenotype of MODY5, in which mutations in the HNF1B gene have been reported. Our genetic testing failed to detect any mutation or microdeletion in the coding or minimal promoter regions of the HNF1B gene. Although there remains a possibility that genetic mutations in introns and regulatory regions of the HNF1B gene might cause the MODY5-like manifestations in this patient, these results might suggest involvement of genes other than HNF1B in the pathogenesis of our patient's disease.
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http://dx.doi.org/10.1507/endocrj.EJ20-0038DOI Listing
September 2020

A frequent nonsense mutation in exon 1 across certain HLA-A and -B alleles in leukocytes of patients with acquired aplastic anemia.

Haematologica 2021 06 1;106(6):1581-1590. Epub 2021 Jun 1.

Department of Hematology, Kanazawa University, Kanazawa, Japan.

Leukocytes that lack HLA allelic expression are frequently detected in patients with acquired aplastic anemia (AA) who respond to immunosuppressive therapy (IST), although the exact mechanisms underlying the HLA loss and HLA allele repertoire likely to acquire loss-of-function mutations are unknown. We identified a common nonsense mutation at position 19 (c.19C>T, p.R7X) in exon 1 (Exon1mut) of different HLA-A and -B alleles in HLA-lacking granulocytes from AA patients. A droplet digital PCR (ddPCR) assay capable of detecting as few as 0.07% Exon1mut HLA alleles in total DNA revealed the mutation was present in 29% (101/353) of AA patients, with a median allele frequency of 0.42% (range, 0.071% to 21.3%). Exon1mut occurred in only 12 different HLA-A (n=4) and HLA-B (n=8) alleles, including B*40:02 (n=31) and A*02:06 (n=15), which correspond to 4 HLA supertypes (A02, A03, B07, and B44). The percentages of patients who possessed at least one of these 12 HLA alleles were significantly higher in the 353 AA patients (92%, P.
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http://dx.doi.org/10.3324/haematol.2020.247809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168509PMC
June 2021

A catalog of the pathogenic mutations of LDL receptor gene in Japanese familial hypercholesterolemia.

J Clin Lipidol 2020 May - Jun;14(3):346-351.e9. Epub 2020 Mar 24.

Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan.

Background: Little data exist on the pathogenic mutations of LDL receptor in Japanese familial hypercholesterolemia (FH).

Objective: We aimed to catalog the pathogenic mutations of LDL receptor gene in the 2 major Japanese FH-care centers (Kanazawa University and National Cerebral and Cardiovascular Center Research Institute), where genetic testing of FH has been performed centrally on requests from institutes all over Japan during more than past 2 decades.

Methods: 796 FH subjects from 472 families who had nonsynonymous mutations in LDL receptor gene were included in this study. Genetic mutations were analyzed for mutations by Sanger sequencing as well as by multiplex ligation probe dependent amplification technique for large rearrangements. Pathogenic mutations were defined either as 1) protein truncated variants, 2) registered as pathogenic in ClinVar, or Human Gene Mutation Database (HGMD), or meet the criteria of American College of Medical Genetics and Genomics guideline, or 3) CADD score > 10.

Results: We found 138 different mutations. Among them, 132 mutations were considered as pathogenic, including 19 large rearrangement mutations. However, 6 missense mutations were classified as variants of unknown significance. A single mutation accounted for as much as 41% of the FH subjects recruited from Kanazawa University mainly due to founder gene effect, whereas many singleton mutations were found from National Cerebral and Cardiovascular Center Research Institute located in Osaka.

Conclusions: We provided the largest catalog of pathogenic mutations of LDL receptor gene in Japanese FH. This could aid to determine the pathogenicity of the LDL receptor genetic mutations not only in Japanese but also in other ethnicities.
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http://dx.doi.org/10.1016/j.jacl.2020.03.002DOI Listing
August 2021

HLA loci predisposing to immune TTP in Japanese: potential role of the shared ADAMTS13 peptide bound to different HLA-DR.

Blood 2020 06;135(26):2413-2419

Department of Blood Transfusion Medicine, Nara Medical University, Kashihara, Japan.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare autoimmune disorder caused by neutralizing anti-ADAMTS13 autoantibodies. In white individuals, HLA allele DRB1*11 is a predisposing factor for iTTP, whereas DRB1*04 is a protective factor. However, the role of HLA in Asians is unclear. In this study, we analyzed 10 HLA loci using next-generation sequencing in 52 Japanese patients with iTTP, and the allele frequency in the iTTP group was compared with that in a Japanese control group. We identified the following HLA alleles as predisposing factors for iTTP in the Japanese population: DRB1*08:03 (odds ratio [OR], 3.06; corrected P [Pc] = .005), DRB3/4/5*blank (OR, 2.3; Pc = .007), DQA1*01:03 (OR, 2.25; Pc = .006), and DQB1*06:01 (OR,: 2.41; Pc = .003). The estimated haplotype consisting of these 4 alleles was significantly more frequent in the iTTP group than in the control group (30.8% vs 6.0%; Pc < .001). DRB1*15:01 and DRB5*01:01 were weak protective factors for iTTP (OR, 0.23; Pc = .076; and OR, 0.23, Pc = .034, respectively). On the other hand, DRB1*11 and DRB1*04 were not associated with iTTP in the Japanese. These findings indicated that predisposing and protective factors for iTTP differ between Japanese and white individuals. HLA-DR molecules encoded by DRB1*08:03 and DRB1*11:01 have different peptide-binding motifs, but interestingly, bound to the shared ADAMTS13 peptide in an in silico prediction model.
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http://dx.doi.org/10.1182/blood.2020005395DOI Listing
June 2020

Subtype-specific gout susceptibility loci and enrichment of selection pressure on and identified by subtype genome-wide meta-analyses of clinically defined gout patients.

Ann Rheum Dis 2020 05 1;79(5):657-665. Epub 2020 Apr 1.

Department of Preventive Medicine and Public Health, National Defense Medical College, Tokorozawa, Japan.

Objectives: Genome-wide meta-analyses of clinically defined gout were performed to identify subtype-specific susceptibility loci. Evaluation using selection pressure analysis with these loci was also conducted to investigate genetic risks characteristic of the Japanese population over the last 2000-3000 years.

Methods: Two genome-wide association studies (GWASs) of 3053 clinically defined gout cases and 4554 controls from Japanese males were performed using the Japonica Array and Illumina Array platforms. About 7.2 million single-nucleotide polymorphisms were meta-analysed after imputation. Patients were then divided into four clinical subtypes (the renal underexcretion type, renal overload type, combined type and normal type), and meta-analyses were conducted in the same manner. Selection pressure analyses using singleton density score were also performed on each subtype.

Results: In addition to the eight loci we reported previously, two novel loci, and , were identified at a genome-wide significance level (p<5.0×10) from a GWAS meta-analysis of all gout patients, and other two novel intergenic loci, and , from normal type gout patients. Subtype-dependent patterns of Manhattan plots were observed with subtype GWASs of gout patients, indicating that these subtype-specific loci suggest differences in pathophysiology along patients' gout subtypes. Selection pressure analysis revealed significant enrichment of selection pressure on in addition to loci for all subtypes except for normal type gout.

Conclusions: Our findings on subtype GWAS meta-analyses and selection pressure analysis of gout will assist elucidation of the subtype-dependent molecular targets and evolutionary involvement among genotype, phenotype and subtype-specific tailor-made medicine/prevention of gout and hyperuricaemia.
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http://dx.doi.org/10.1136/annrheumdis-2019-216644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7213308PMC
May 2020

A homozygous SFTPA1 mutation drives necroptosis of type II alveolar epithelial cells in patients with idiopathic pulmonary fibrosis.

J Exp Med 2019 12 10;216(12):2724-2735. Epub 2019 Oct 10.

Department of Immunology & Parasitology, Graduate School of Medicine, Tokushima University, Tokushima, Japan

Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by scattered fibrotic lesions in the lungs. The pathogenesis and genetic basis of IPF remain poorly understood. Here, we show that a homozygous missense mutation in caused IPF in a consanguineous Japanese family. The mutation in disturbed the secretion of SFTPA1 protein. Sftpa1 knock-in (Sftpa1-KI) mice that harbored the same mutation as patients spontaneously developed pulmonary fibrosis that was accelerated by influenza virus infection. Sftpa1-KI mice showed increased necroptosis of alveolar epithelial type II (AEII) cells with phosphorylation of IRE1α leading to JNK-mediated up-regulation of Ripk3. The inhibition of JNK ameliorated pulmonary fibrosis in Sftpa1-KI mice, and overexpression of Ripk3 in Sftpa1-KI mice treated with a JNK inhibitor worsened pulmonary fibrosis. These findings provide new insight into the mechanisms of IPF in which a mutation in promotes necroptosis of AEII cells through JNK-mediated up-regulation of Ripk3, highlighting the necroptosis pathway as a therapeutic target for IPF.
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http://dx.doi.org/10.1084/jem.20182351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6888986PMC
December 2019

Tissue-specific autoimmunity controlled by Aire in thymic and peripheral tolerance mechanisms.

Int Immunol 2020 02;32(2):117-131

Division of Molecular Immunology, Institute for Enzyme Research, Tokushima University, Tokushima, Japan.

Tissue-specific autoimmune diseases are assumed to arise through malfunction of two checkpoints for immune tolerance: defective elimination of autoreactive T cells in the thymus and activation of these T cells by corresponding autoantigens in the periphery. However, evidence for this model and the outcome of such alterations in each or both of the tolerance mechanisms have not been sufficiently investigated. We studied these issues by expressing human AIRE (huAIRE) as a modifier of tolerance function in NOD mice wherein the defects of thymic and peripheral tolerance together cause type I diabetes (T1D). Additive huAIRE expression in the thymic stroma had no major impact on the production of diabetogenic T cells in the thymus. In contrast, huAIRE expression in peripheral antigen-presenting cells (APCs) rendered the mice resistant to T1D, while maintaining other tissue-specific autoimmune responses and antibody production against an exogenous protein antigen, because of the loss of Xcr1+ dendritic cells, an essential component for activating diabetogenic T cells in the periphery. These results contrast with our recent demonstration that huAIRE expression in both the thymic stroma and peripheral APCs resulted in the paradoxical development of muscle-specific autoimmunity. Our results reveal that tissue-specific autoimmunity is differentially controlled by a combination of thymic function and peripheral tolerance, which can be manipulated by expression of huAIRE/Aire in each or both of the tolerance mechanisms.
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http://dx.doi.org/10.1093/intimm/dxz066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005526PMC
February 2020

Next-generation sequencing identifies contribution of both class I and II HLA genes on susceptibility of multiple sclerosis in Japanese.

J Neuroinflammation 2019 Aug 5;16(1):162. Epub 2019 Aug 5.

Department of Neurology, Osaka University Graduate School of Medicine, Suita, 565-0871, Japan.

Background: The spectrum of classical and non-classical HLA genes related to the risk of multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) in the Japanese population has not been studied in detail. We conducted a case-control analysis of classical and non-classical HLA genes.

Methods: We used next-generation sequencing (NGS)-based HLA genotyping methods for mapping risk for 45 MS patients, 31 NMOSD patients, and 429 healthy controls. We evaluated the association of the HLA variants with the risk of MS and NMOSD using logistic regression analysis and Fisher's exact test.

Results: We confirmed that HLA-DRB1*15:01 showed the strongest association with MS (P = 2.1 × 10; odds ratio [OR] = 3.44, 95% confidence interval [95% CI] = 1.95-6.07). Stepwise conditional analysis identified HLA-DRB1*04:05, HLA-B*39:01, and HLA-B*15:01 as being associated with independent MS susceptibility (P < 8.3 × 10). With respect to amino acid polymorphisms in HLA genes, we found that phenylalanine at HLA-DQβ1 position 9 had the strongest effect on MS susceptibility (P = 3.7 × 10, OR = 3.48, 95% CI = 2.23-5.43). MS risk at HLA-DQβ1 Phe9 was independent of HLA-DRB1*15:01 (P = 1.5 × 10, OR = 2.91, 95% CI = 1.79-4.72), while HLA-DRB1*15:01 was just significant when conditioned on HLA-DQβ1 Phe9 (P = 0.037). Regarding a case-control analysis for NMOSD, HLA-DQA1*05:03 had a significant association with NMOSD (P = 1.5 × 10, OR = 6.96, 95% CI = 2.55-19.0).

Conclusions: We identified HLA variants associated with the risk of MS and NMOSD. Our study contributes to the understanding of the genetic architecture of MS and NMOSD in the Japanese population.
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http://dx.doi.org/10.1186/s12974-019-1551-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683481PMC
August 2019

New PCNT candidate missense variant in a patient with oral and maxillofacial osteodysplasia: a case report.

BMC Med Genet 2019 07 16;20(1):126. Epub 2019 Jul 16.

Department of Pediatric Imaging, Tokyo Metropolitan Children's Medical Center, 2-8-29 Musashidai, Fuchu, Tokyo, 183-8561, Japan.

Background: Osteodysplasia of the oral and maxillofacial bone is generally accompanied by systemic bone abnormalities (such as short stature, joint contracture) or other systemic abnormalities (such as renal, dermatological, cardiovascular, optic, or hearing disorders). However, it does not always present this way. Recent reports have suggested that genome-wide sequencing is an effective method for identifying rare or new disorders. Here, we performed whole-exome sequencing (WES) in a patient with a unique form of acquired, local osteodysplasia of the oral and maxillofacial region.

Case Presentation: A 46-year-old woman presented to our hospital with the complaint of gradually moving mandibular teeth (for 6 months), changing facial appearance, and acquired osteolysis of the oral and maxillofacial bones, showing mandibular hypoplasia without family history. Upon skeletal examination, there were no abnormal findings outside of the oral and maxillofacial area; the patient had a height of 157 cm and bone mineral density (according to dual energy x-ray absorptiometry) of 90%. Results of blood and urine tests, including evaluation of bone metabolism markers and neurological and cardiovascular examinations, were normal. We performed WES of genomic DNA extracted from the blood of this patient and her mother, who did not have the disease, as a negative control. We identified 83 new missense variants in the patient, not detected in her mother, including a candidate single nucleotide variant in exon 14 of PCNT (pericentrin). Critical homozygous or compound heterozygous variants in PCNT are a known cause of microcephalic osteodysplastic primordial dwarfism type II accompanied by mandibular hypoplasia, which is similar to the maxillofacial phenotype in this patient.

Conclusions: Protein simulations performed using Polymorphism Phenotyping v2 and Combined Annotation Dependent Depletion software indicated that this missense variant is likely to disrupt the PCNT protein structure. These results suggest that this is a new form of osteolysis related to this PCNT variant.
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http://dx.doi.org/10.1186/s12881-019-0858-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6636042PMC
July 2019
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