Yasushi Okazaki

Juntendo University · Intractable Disease Research Center

Background The mitochondrial contact site and cristae organising system (MICOS) complex is required for cristae formation and is composed of seven proteins. Among the genes of MICOS complex, variants of MICOS13 , IMMT and APOO have been reported to cause diseases. Methods and Results We report a case in which whole genome sequencing identified a v...

Introduction The SARS-CoV-2 pandemic has had a widespread and severe impact on society, yet there have also been instances of remarkable recovery, even in critically ill patients. Materials and methods In this study, we used single-cell RNA sequencing to analyze the immune responses in recovered and deceased COVID-19 patients during moderate and c...

Objectives: Serrated polyposis syndrome (SPS) is a rare condition associated with an increased risk of colorectal cancer. However, the genetic basis of SPS in Japanese patients remains unclear. The present study therefore aimed to address this omission by identifying candidate causative genes of SPS in Japanese patients. Methods: The present study...

We identified bi-allelic novel GGGCC repeat expansion as long as ~200 repeats in the promoter region of NAXE in a unidentified mitochondrial disease patient in a Japanese cohort of mitochondrial diseases. NAXE is known to be responsible for NAXE-related mitochondrial encephalopathy. The promoter region of NAXE was CpG hyper-methylated, revealed by...

Nonhuman primates (NHPs), which are closely related to humans, are useful in biomedical research, and an increasing number of NHP disease models have been reported using gene editing. However, many disease-related genes cause perinatal death when manipulated homozygously by gene editing. In addition, NHP resources, which are limited, should be effi...

The precise diagnosis and medical management of patients with suspected familial adenomatous polyposis should be based on genetic testing, which may not always be available. Therefore, establishing a new model for predicting the likelihood of a germline pathogenic variant (GPV) of APC based on its clinical manifestations could prove to be useful in...

The alignment of each cell in human myocardium is considered critical for the efficient movement of cardiac tissue. We investigated 96-well microstripe-patterned plates to align human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs), which resemble fetal myocardium. The aligned CMs (ACMs) cultured on the microstripe-patterned plat...

The SARS-CoV-2 pandemic has had a widespread and severe impact on society, yet there have also been instances of remarkable recovery, even in critically ill patients. In this study, we used single-cell RNA sequencing to analyze the immune responses in recovered and deceased COVID-19 patients during moderate and critical stages. The study included t...

Isolated complex I (CI) deficiencies are a major cause of primary mitochondrial disease. A substantial proportion of CI deficiencies are believed to arise from defects in CI assembly factors (CIAFs) that are not part of the CI holoenzyme. The biochemistry of these CIAFs is poorly defined, making their role in CI assembly unclear, and confounding in...

The human genome is pervasively transcribed and produces a wide variety of long non-coding RNAs (lncRNAs), constituting the majority of transcripts across human cell types. Some specific nuclear lncRNAs have been shown to be important regulatory components acting locally. As RNA-chromatin interaction and Hi-C chromatin conformation data showed that...

Autosomal recessive pathogenetic variants in the DGUOK gene cause deficiency of deoxyguanosine kinase activity and mitochondrial deoxynucleotides pool imbalance, consequently, leading to quantitative and/or qualitative impairment of mitochondrial DNA synthesis. Typically, patients present early-onset liver failure with or without neurological invol...

Background Based on molecular characteristics, deficient DNA mismatch repair (dMMR) solid tumors are largely divided into three categories: somatically MLH1 -hypermethylated tumors, Lynch syndrome (LS)-associated tumors, and Lynch-like syndrome (LLS)-associated tumors. The incidence of each of these conditions and the corresponding pathogenic genes...

75 Background: Serrated polyposis syndrome (SPS) is a rare condition associated with an increased risk of colorectal cancer. Previous studies have identified germline truncating variants of the RNF43; however, patients harboring these variants comprise a small part of those with SPS, in most of whom the causative gene remains unknown. To date, no s...

Isolated complex I (CI) deficiencies are a major cause of primary mitochondrial disease. Two-thirds of CI deficiencies arise from defects in CI assembly factors (CIAFs) that are not part of the CI holoenzyme. The biochemistry of CIAFs is poorly defined, making their role in CI assembly unclear and confounding interpretation of potential disease-cau...

Transcribed cis-regulatory elements (tCREs), such as promoters and enhancers, are fundamental to modulate gene expression and define cell identity. The detailed mapping of tCREs at single-cell resolution is essential for understanding the regulatory mechanisms that govern cellular functions. Prior tCRE catalogs, limited by bulk analysis, have often...

Cowden syndrome (CS) /PTEN hamartoma tumor syndrome (PHTS) is a rare autosomal dominantly inherited condition caused by germline pathogenesis. It is associated with multiple hamartomatous lesions occurring in various organs and tissues, including the gastrointestinal tract, skin, mucous membranes, breast, thyroid, endometrium, and brain. Macrocepha...

While some old adults stay healthy and non-frail up to late in life, others experience multimorbidity and frailty often accompanied by a pro-inflammatory state. The underlying molecular mechanisms for those differences are still obscure. Here, we used gene expression analysis to understand the molecular underpinning between non-frail and frail indi...

Biallelic KARS1 mutations cause KARS-related diseases, a rare syndromic condition encompassing central and peripheral nervous system impairment, heart and liver disease, and deafness. KARS1 encodes the t-RNA synthase of lysine, an aminoacyl-tRNA synthetase, involved in different physiological mechanisms (such as angiogenesis, post-translational mod...

Oxidative phosphorylation defects results in mitochondrial diseases, with cardiac involvement markedly impacting prognosis. However, the mechanisms underlying the transition from compensation to dysfunction in response to metabolic deficiency remain unclear, impeding the development of effective treatments. Here, we employed single-nucleus RNA sequ...

Linear IgA disease (LAD) is a rare autoimmune bullous disease characterized by IgA deposition in the basement membrane zone (BMZ). A 66-year-old male was treated for myelodysplastic syndrome at our hospital for 5 years, during which his condition remained stable. He visited our department because of erythema with itching, which appeared 1 year ago...

Limited mouth opening is a characteristic of masticatory muscle tendon-aponeurosis hyperplasia (MMTAH). Although genetic involvement is suspected where familial onset is frequently observed, the genetic background of MMTAH is yet to be elucidated. In this study, we conducted whole genome sequencing of 10 patients with MMTAH and their family members...

A 26-year-old woman developed a sudden headache, ptosis, and diplopia. Magnetic resonance imaging and angiography demonstrated a symmetrical lesion from the midbrain to the brainstem, involving the solitary nucleus and multifocal cerebral artery narrowing. Reversible cerebral vasospasm syndrome (RCVS) was suspected, and the patient improved after v...

Background: Autosomal dominant polycystic kidney disease (ADPKD) occurs in 1 in 500-4000 people worldwide. Genetic mutation is a biomarker for predicting renal dysfunction in patients with ADPKD. In this study, we performed a genetic analysis of Japanese patients with ADPKD to investigate the prognostic utility of genetic mutations in predicting r...

Background: SLCO2A1 encodes a prostaglandin (PG) transporter, and autosomal recessive pathogenic variants of this gene cause chronic enteropathy associated with SLCO2A1. It is unclear whether a heterozygous pathogenic variant of SLCO2A1 has a role in the pathogenesis of other types of inflammatory bowel disease (IBD). In this study, we investigate...

Attenuated familial adenomatous polyposis, which accounts for ~10% of familial adenomatous polyposis, is difficult to diagnose because of its milder course and later onset. In both familial adenomatous polyposis and attenuated familial adenomatous polyposis, duodenal cancer is usually recognized 10-20 years after the diagnosis of colonic polyposis....

Approximately 80% of rare diseases have a genetic cause, and an accurate genetic diagnosis is necessary for disease management, prognosis prediction, and genetic counseling. Whole-exome sequencing (WES) is a cost-effective approach for exploring the genetic cause, but several cases often remain undiagnosed. We combined whole genome sequencing (WGS)...

Juvenile polyposis syndrome (JPS) is a rare disease characterized by multiple hamartomatous polyps within the gastrointestinal tract. SMAD4 or BMPR1A is known as a causative gene of JPS. Approximately 75% of newly diagnosed cases have an autosomal-dominantly inherited condition, whereas 25% are sporadic without previous history of polyposis in the...

Background Enoyl-CoA hydratase short-chain 1 (ECHS1) is an enzyme involved in the metabolism of branched chain amino acids and fatty acids. Mutations in the ECHS1 gene lead to mitochondrial short-chain enoyl-CoA hydratase 1 deficiency, resulting in the accumulation of intermediates of valine. This is one of the most common causative genes in mitoch...

Background: Peutz-Jeghers syndrome (PJS) is a rare disease characterized by the presence of hamartomatous polyposis throughout the gastrointestinal tract, except for the esophagus, along with characteristic mucocutaneous pigmentation. It is caused by germline pathogenic variants of the STK11 gene, which exhibit an autosomal dominant mode of inheri...

Although gastric juvenile polyposis (GJP) often coexists with gastric cancer, a preoperative accurate diagnosis is still difficult to obtain. A 70-year-old woman was referred for epigastralgia and anemia. Esophagogastroduodenoscopy with a conventional endoscope showed numerous gastric polyps with no cancerous findings. Magnifying endoscopy with nar...

The identification of the m.12207G > A variant in MT-TS2, (NC_012920.1:m.12207G > A) was first reported in 2006. The affected individual presented with developmental delay, feeding difficulty, proximal muscle weakness, and lesions within her basal ganglia, with heteroplasmy levels of 92% in muscle and no evidence of maternal inheritance. Herein, we...

NADH dehydrogenase 5 (ND5) is one of 44 subunits composed of Complex I in mitochondrial respiratory chain. Therefore, a mitochondrially encoded ND5 (MT-ND5) gene mutation causes mitochondrial oxidative phosphorylation (OXPHOS) disorder, resulting in the development of mitochondrial diseases. Focal segmental glomerulosclerosis (FSGS) which had podoc...

Background: There is a lack of information on rare germline variants of pancreatic cancer-predisposing genes. Risk genes for multiple primary cancers may overlap with those for pancreatic cancer. Methods: A retrospective study of autopsy cases with a negative family history in the Japanese single nucleotide polymorphism for geriatric research da...

Coenzyme Q10 (CoQ10) is involved in ATP production through electron transfer in the mitochondrial respiratory chain complex. CoQ10 receives electrons from respiratory chain complex I and II to become the reduced form, and then transfers electrons at complex III to become the oxidized form. The redox state of CoQ10 has been reported to be a marker o...

The m.3243A > G mutation in the mitochondrially encoded tRNA leucine 1 (MT-TL1) gene is known to cause mitochondrial nephropathy. However, its long-term effects of the m.3243A > G mutation on renal histopathology or heteroplasmy rates remain unknown. Here we present the case of a female patient who underwent renal biopsy at 34 years of age to inves...

Objectives: Recently, a genetic risk for chronic pancreatitis (CP) was found to be conferred by pathogenic variants in the transient receptor potential cation channel, subfamily V, member 6 (TRPV6). Interestingly, 20-57% of patients with functionally defective TRPV6 variants have other susceptibility genes such as cationic trypsinogen (PRSS1), ser...

Juvenile polyposis syndrome (JPS) is an autosomal dominant, inherited disorder caused by pathogenic germline variants of mainly SMAD4 or BMPR1A genes. Some patients with JPS, especially with SMAD4 variants, also develop hereditary, hemorrhagic telangiectasia (HHT). HHT is also an autosomal dominant inherited disorder. Herein, we identified a novel...

Background Mycetoma is a neglected, chronic granulomatous infection of the subcutaneous tissue, most often caused by the fungal pathogen Madurella mycetomatis. Characteristic of the infection is the formation of grains. However, knowledge of the function and formation of the grain is limited. To map the processes leading to M. mycetomatis grain for...

Biallelic deletions extending into the ATPase family AAA-domain containing protein 3A (ATAD3A) gene lead to infantile lethality with severe pontocerebellar hypoplasia (PCH). However, only 12 such cases have been reported worldwide to date, and the genotype–phenotype correlations are not well understood. We describe cases associated with the same no...

Within the scope of the FANTOM6 consortium, we perform a large-scale knockdown of 200 long non-coding RNAs (lncRNAs) in human induced pluripotent stem cells (iPSCs) and systematically characterize their roles in self-renewal and pluripotency. We find 36 lncRNAs (18%) exhibiting cell growth inhibition. From the knockdown of 123 lncRNAs with transcri...

Li-Fraumeni syndrome(LFS)is a hereditary cancer disorder caused by germline variant in TP53 and characterized by various malignancies. Multidisciplinary treatment is needed for tumors of LFS, however, radiation therapy is a relative contraindication because of frequent development of secondary malignancy such as sarcoma in the irradiated field. Cas...

Infantile striatonigral degeneration is caused by a homozygous variant of the nuclear‐pore complex (NPC) gene NUP62, involved in nucleo‐cytoplasmic trafficking. By querying sequencing‐datasets of patients with dystonia and/or Leigh(‐like) syndromes, we identified three unrelated individuals with biallelic variants in NUP54. All variants clustered i...

ECHS1 is the causative gene for mitochondrial short-chain enoyl-CoA hydratase 1 deficiency. While genetic analysis studies have diagnosed numerous cases with ECHS1 variants, the increasing number of variants of uncertain significance (VUS) in genetic diagnosis is a major problem. Therefore, we constructed an assay system to verify VUS function. A h...

Hypertrophic cardiomyopathy is a common cardiac complication in mitochondrial disorders, and the morbidity rate in neonatal cases is up to 40%. The mortality rate within 3 months for neonatal-onset mitochondrial cardiomyopathy is known to be high because there is currently no established treatment. We report the case of a male infant with neonatal-...

Biotin-responsive basal ganglia disease (BBGD) with SLC19A3 mutation was first reported in 1998, and over 30 mutations have been reported. We report a neonatal BBGD case with sudden-onset feeding difficulty and impaired consciousness. Encephalopathy resolved after the initiation of biotin and thiamine treatment. Genetic testing revealed a novel het...

Patients with end-stage renal disease (ESRD) or receiving dialysis have a much higher risk for renal cell carcinoma (RCC), but carcinogenic mechanisms and genomic features remain little explored and undefined. This study’s goal was to identify the genomic features of ESRD RCC and characterize them for associations with tumor histology and dialysis...

Pathogenic mitochondrial DNA heteroplasmy has mainly been assessed with bulk sequencing in individuals with mitochondrial disease. However, the distribution of heteroplasmy at the single‐cell level in skin fibroblasts obtained from individuals, together with detailed clinical and biochemical information, remains to be investigated. We used the mito...

Abstract Background Hypopharyngeal cancer is a relatively rare malignancy with poor prognosis. Current chemotherapeutic algorithm is still far from personalized medicine, and the identification of the truly active therapeutic biomarkers and/or targets is eagerly awaited. Methods Venturing to focus on the conventional key chemotherapeutic drugs, we...

Smoking is a known risk factor for the development of colorectal polyps. Even in familial adenomatous polyposis and serrated polyposis syndrome, smoking is a risk factor of the development of polyps. Here, we report a case of monozygotic twins with atypical colorectal polyposis showing lots of hyperplastic polyps and adenomas and describe how the p...

Background Lack of functional evidence hampers variant interpretation, leaving a large proportion of individuals with a suspected Mendelian disorder without genetic diagnosis after whole genome or whole exome sequencing (WES). Research studies advocate to further sequence transcriptomes to directly and systematically probe gene expression defects....

Precision medicine using exome and whole-genome sequences has grown exponentially in the clinical setting, and many laboratories are putting sequencing into their portfolio of diagnostics. The cost of whole genome sequencing has come to be less than one thousand dollars per person, but in order to analyze it and interpret its clinical significance,...

Background: This study aimed to assess current trends in morbidity and mortality among patients with familial adenomatous polyposis (FAP). These data can be used for optimal surveillance and management of such patients. Methods: Data (November 2001 and April 2020) of genetically confirmed patients with FAP (n = 87) and their first-degree relativ...

Collagen type XVII α1 (COL17A1) encodes a hemidesmosomal protein at the epidermal-dermal junction and its variants are implicated in blistering skin diseases. Recent experiments in rodents revealed that Col17a1 has critical roles in stem cells of epidermal origin and in melanoma carcinogenesis. In the present study, it was investigated whether germ...

Short-chain enoyl-CoA hydratase (ECHS1) is involved in amino acid and fatty acid catabolism in mitochondria and its deficiency causes Leigh syndrome or exercise-induced dystonia. More than 60 patients with this condition have been reported till date. The accumulation of intermediate metabolites of valine is assumed to be responsible for the cytotox...

The m.14453G>A mutation in MT-ND6 has been described in a few patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes or Leigh syndrome. However, the clinical spectrum and molecular characteristics are unclear. Here, we present four infantile-onset patients with m.14453G>A-associated Leigh syndrome. All four patient...

Background: Alzheimer's disease (AD) is the leading cause of dementia worldwide. Despite the considerable research efforts, exact pathomechanisms still remain unknown, and no effective treatment is available. AD research field have mainly utilized mouse models for decades, but species differences between rodents and primates may constrain us from...

Spinocerebellar ataxia type 34 (SCA34) is an autosomal dominant inherited ataxia due to mutations in ELOVL4, which encodes one of the very long-chain fatty acid elongases. SCA38, another spinocerebellar ataxia, is caused by mutations in ELOVL5, a gene encoding another elongase. However, there have been no previous studies describing the neuropathol...

Objective: Neonatal-onset mitochondrial disease has not been fully characterised owing to its heterogeneity. We analysed neonatal-onset mitochondrial disease in Japan to clarify its clinical features, molecular diagnosis and prognosis. Design: Retrospective observational study from January 2004 to March 2020. Setting: Population based. Patien...

Isolated complex I deficiency is the most common cause of pediatric mitochondrial disease. Exome sequencing (ES) has revealed many complex I causative genes. However, there are limitations associated with identifying causative genes by ES analysis. In this study, we performed multi-omics analysis to reveal the causal variants. We here report two ca...

The production of pancreatic β cells is the most challenging step for curing diabetes using next-generation treatments. Adult pancreatic endocrine cells are thought to be maintained by the self-duplication of differentiated cells, and pancreatic endocrine neogenesis can only be observed when the tissue is severely damaged. Experimentally, this can...

Trio-next generation sequencing is useful to identify undiagnosed inherited diseases. We have attended a patient with trigenic ADH5 / ALDH2 / ADGRV1 pathogenic variants, which caused two distinct diseases, myelodysplastic syndrome and Usher syndrome. Whole genome sequencing of peripheral blood from the patient and his parents were applied to identi...

Next-generation sequencing of oral squamous cell carcinoma (OSCC) has revealed TP53 as the most frequently mutated gene in OSCC mutually exclusive with human papillomavirus infection. Oral epithelial dysplasia (OED) is defined as a precancerous lesion of OSCC by the current World Health Organization (WHO) classification; therefore, it is assumed th...

Background The prevalence of Lynch syndrome (LS)-associated DNA mismatch repair (MMR)-deficient bladder cancer (BC) has scarcely been investigated.Methods Immunohistochemistry for four MMR proteins (MLH1, MSH2, MSH6, and PMS2) was performed in formalin-fixed paraffin-embedded (FFPE) sections prepared from the resected specimens of 618 consecutive n...

Background Cardiomyopathy is a risk factor for poor prognosis in pediatric patients with mitochondrial disease. However, other risk factors including genetic factors related to poor prognosis in mitochondrial disease has yet to be fully elucidated. Methods and results Between January 2004 and September 2019, we enrolled 223 consecutive pediatric m...