ABSTRACT
MYH9-related disorders are a group of autosomal dominant disorders caused by mutations in MYH9, and are characterized by thrombocytopenia, sensorineural hearing loss, cataracts, and renal failure. Here, we report a case of chronic renal failure due to MYH9-related disorder with renal symptoms in a patient who underwent living-donor renal transplantation. The patient was diagnosed with proteinuria during a health checkup at the age of 12 years. Her renal function gradually deteriorated, and hemodialysis was initiated at 34 years of age. No definitive diagnosis of renal disease was made through renal biopsy. At the age of 35, she underwent living-donor renal transplantation from her mother as the donor. Six years after transplantation, her renal function remained stable, and no evidence of recurrent nephritis was found during renal biopsies. The family history revealed that her father, uncle, and younger brother had end-stage kidney disease. Genetic testing revealed a mutation (p.E1653D) related to the MYH9 gene. As her father had a history of renal biopsy and was diagnosed with focal segmental glomerulosclerosis (FSGS), we diagnosed chronic renal failure due to FSGS associated with MYH9 disorder. There were no findings suggestive of hearing loss, cataracts, or thrombocytopenia in the recipient or their family members with renal failure, and no symptoms other than renal failure were noted.
ABSTRACT
Germline loss-of-function mutations in USP9X have been reported to cause a wide spectrum of congenital anomalies. Here, we report a Japanese girl with a novel heterozygous nonsense mutation in USP9X who exhibited intellectual disability with characteristic craniofacial abnormalities, including hypotelorism, brachycephaly, hypodontia, micrognathia, severe dental crowding, and an isolated submucous cleft palate. Our findings provide further evidence that disruptions in USP9X contribute to a broad range of congenital craniofacial abnormalities.
ABSTRACT
GJA1 is the causative gene for oculodentodigital dysplasia (ODDD). A novel de novo GJA1 variant, NM 000165:c263C > T [p.P88L], was identified in a mosaic state in a patient with short stature, seizures, delayed myelination, mild hearing loss, and tooth enamel hypoplasia. Although the patient exhibited severe neurodevelopmental delay, other clinical features of ODDD, including limb anomalies, were mild. This may be due to differences in the mosaic ratios in different organs.
ABSTRACT
Cardiac sarcoidosis (CS) is the scarring of heart muscles by autoimmunity, leading to heart abnormalities and patients with sarcoidosis with cardiac involvements have poor prognoses. Due to the small number of patients, it is difficult to stratify all patients of CS by human leukocyte antigen (HLA) analysis. We focused on the structure of antigen-recognizing pockets in heterodimeric HLA-class II, in addition to DNA sequences, and extracted high-affinity combinations of antigenic epitopes from candidate autoantigen proteins and HLA. Four HLA heterodimer-haplotypes (DQA1*05:03/05:05/05:06/05:08-DQB1*03:01) were identified in 10 of 68 cases. Nine of the 10 patients had low left ventricular ejection fraction (< 50%). Fourteen amino-acid sequences constituting four HLA anchor pockets encoded by the HLA haplotypes were all common, suggesting DQA1*05:0X-DQB1*03:01 exhibit one group of heterodimeric haplotypes. The heterodimeric haplotypes recognized eight epitopes from different proteins. Assuming that autoimmune mechanisms might be activated by molecular mimicry, we searched for bacterial species having peptide sequences homologous to the eight epitopes. Within the peptide epitopes form the SLC25A4 and DSG2, high-homology sequences were found in Cutibacterium acnes and Mycobacterium tuberculosis, respectively. In this study, we detected the risk heterodimeric haplotypes of ventricular dysfunction in CS by searching for high-affinity HLA-class II and antigenic epitopes from candidate cardiac proteins.
Subject(s)
Sarcoidosis , Ventricular Dysfunction, Left , Humans , Haplotypes , Stroke Volume , HLA-DQ alpha-Chains/genetics , HLA-DQ beta-Chains/genetics , Ventricular Function, Left , HLA-DQ Antigens/genetics , Histocompatibility Antigens Class I/genetics , Sarcoidosis/genetics , Epitopes , Ventricular Dysfunction, Left/genetics , Peptides/genetics , HLA-DRB1 Chains/genetics , Gene Frequency , Alleles , Genetic Predisposition to DiseaseABSTRACT
Tricho-rhino-phalangeal syndrome type I (TRPS1), caused by pathogenic variants in the transcriptional repressor GATA-binding 1 gene (TRPS1), is characterized by ectodermal and skeletal anomalies including short stature and sparse scalp hair during infancy. TRPS1 encodes a zinc finger protein transcription factor that contributes to bone homeostasis by regulating perichondral mineralization, chondrocyte proliferation, and apoptosis. Here, a male infant aged 14 months presented with sparse scalp hair, deformed nails, fused teeth, and postnatal growth retardation without neurodevelopmental disorder. As endocrinological measurements revealed low serum zinc levels, he was treated with zinc acetate hydrate, which improved his growth velocity and scalp hair. Whole-exome sequencing revealed that this patient harbored a novel pathogenic de novo heterozygous TRPS1 frameshift variant, c.2819_2822del, p.(His940Argfs*6). Zinc deficiency induces zinc finger protein dysfunction via effects on protein folding and assembly, affecting target gene transcription and apoptosis. The symptoms of TRPS1 are similar to those caused by inadequate levels of zinc, an essential trace element with important roles in tissue growth and repair. Accompanying zinc deficiency may have affected the function of important zinc finger proteins, resulting in phenotypic deterioration. Analysis of zinc metabolism in patients harboring TRPS1 variants will enhance understanding the variety of phenotypes of TRPS1.
Subject(s)
DNA-Binding Proteins , Langer-Giedion Syndrome , Humans , Male , DNA-Binding Proteins/genetics , Repressor Proteins/genetics , Transcription Factors/genetics , Langer-Giedion Syndrome/genetics , ZincABSTRACT
We report a Japanese patient with tall stature, dolichocephaly, prominent forehead, narrow nasal ridge, mild retrognathia, subcutaneous fat reduction, bilateral entropion of both eyelids, high arched palate, long fingers, and mild hyperextensible finger joints as a case of Marfanoid-progeroid-lipodystrophy syndrome. Genetic investigation revealed a heterozygous variant NC_000015.10(NM_000138.5):c.8226+5G>A in the FBN1 gene. Skipping of exon 65 and escaping nonsense-mediated decay followed by frameshift were experimentally confirmed in the proband's mRNA.
ABSTRACT
BACKGROUND: Restrictive cardiomyopathy in children is rare and outcomes are very poor. However, little information is available concerning genotype-outcome correlations. METHODS: We analyzed the clinical characteristics and genetic testing, including whole exome sequencing, of 28 pediatric restrictive cardiomyopathy patients who were diagnosed from 1998 to 2021 at Osaka University Hospital in Japan. RESULTS: The median age at diagnosis (interquartile range) was 6 (2.25-8.5) years. Eighteen patients received heart transplantations and 5 patients were on the waiting list. One patient died while waiting for transplantation. Pathologic or likely-pathogenic variants were identified in 14 of the 28 (50%) patients, including heterozygous TNNI3 missense variants in 8 patients. TNNT2, MYL2, and FLNC missense variants were also identified. No significant differences in clinical manifestations and hemodynamic parameters between positive and negative pathogenic variants were detected. However, 2- and 5-year survival rates were significantly lower in patients with pathogenic variants (50% and 22%) compared with survival in patients without pathogenic variants (62% and 54%; P=0.0496, log-rank test). No significant differences were detected in the ratio of patients diagnosed at nationwide school heart disease screening program between positive and negative pathogenic variants. Patients diagnosed by school screening showed better transplant-free survival compared with patients diagnosed by heart failure symptoms (P=0.0027 in log-rank test). CONCLUSIONS: In this study, 50% of pediatric restrictive cardiomyopathy patients had pathogenic or likely-pathogenic gene variants, and TNNI3 missense variants were the most frequent. Patients with pathogenic variants showed significantly lower transplant-free survival compared with patients without pathogenic variants.
Subject(s)
Cardiomyopathy, Restrictive , Heart Diseases , Humans , Child , Cardiomyopathy, Restrictive/diagnosis , Cardiomyopathy, Restrictive/genetics , Genetic Testing , Genotype , Heterozygote , Mutation, Missense , Heart Diseases/geneticsABSTRACT
BACKGROUND: Cardiac-specific myosin light chain kinase (cMLCK), encoded by MYLK3, regulates cardiac contractility through phosphorylation of ventricular myosin regulatory light chain. However, the pathophysiological and therapeutic implications of cMLCK in human heart failure remain unclear. We aimed to investigate whether cMLCK dysregulation causes cardiac dysfunction and whether the restoration of cMLCK could be a novel myotropic therapy for systolic heart failure. METHODS: We generated the knock-in mice (Mylk3+/fs and Mylk3fs/fs) with a familial dilated cardiomyopathy-associated MYLK3 frameshift mutation (MYLK3+/fs) that had been identified previously by us (c.1951-1G>T; p.P639Vfs*15) and the human induced pluripotent stem cell-derived cardiomyocytes from the carrier of the mutation. We also developed a new small-molecule activator of cMLCK (LEUO-1154). RESULTS: Both mice (Mylk3+/fs and Mylk3fs/fs) showed reduced cMLCK expression due to nonsense-mediated messenger RNA decay, reduced MLC2v (ventricular myosin regulatory light chain) phosphorylation in the myocardium, and systolic dysfunction in a cMLCK dose-dependent manner. Consistent with this result, myocardium from the mutant mice showed an increased ratio of cardiac superrelaxation/disordered relaxation states that may contribute to impaired cardiac contractility. The phenotypes observed in the knock-in mice were rescued by cMLCK replenishment through the AAV9_MYLK3 vector. Human induced pluripotent stem cell-derived cardiomyocytes with MYLK3+/fs mutation reduced cMLCK expression by 50% and contractile dysfunction, accompanied by an increased superrelaxation/disordered relaxation ratio. CRISPR-mediated gene correction, or cMLCK replenishment by AAV9_MYLK3 vector, successfully recovered cMLCK expression, the superrelaxation/disordered relaxation ratio, and contractile dysfunction. LEUO-1154 increased human cMLCK activity ≈2-fold in the Vmax for ventricular myosin regulatory light chain phosphorylation without affecting the Km. LEUO-1154 treatment of human induced pluripotent stem cell-derived cardiomyocytes with MYLK3+/fs mutation restored the ventricular myosin regulatory light chain phosphorylation level and superrelaxation/disordered relaxation ratio and improved cardiac contractility without affecting calcium transients, indicating that the cMLCK activator acts as a myotrope. Finally, human myocardium from advanced heart failure with a wide variety of causes had a significantly lower MYLK3/PPP1R12B messenger RNA expression ratio than control hearts, suggesting an altered balance between myosin regulatory light chain kinase and phosphatase in the failing myocardium, irrespective of the causes. CONCLUSIONS: cMLCK dysregulation contributes to the development of cardiac systolic dysfunction in humans. Our strategy to restore cMLCK activity could form the basis of a novel myotropic therapy for advanced systolic heart failure.
Subject(s)
Heart Failure, Systolic , Induced Pluripotent Stem Cells , Humans , Mice , Animals , Myosin-Light-Chain Kinase/genetics , Myosin-Light-Chain Kinase/metabolism , Phosphorylation , Myosin Light Chains/genetics , Myosin Light Chains/metabolism , Induced Pluripotent Stem Cells/metabolism , Myocardium/metabolism , Myocytes, Cardiac/metabolism , Myocardial Contraction/physiology , RNA, Messenger/genetics , Cardiac Myosins/genetics , Cardiac Myosins/metabolismABSTRACT
Craniofacial defects are one of the most frequent phenotypes in syndromic diseases. More than 30% of syndromic diseases are associated with craniofacial defects, which are important for the precise diagnosis of systemic diseases. Special AT-rich sequence-binding protein 2 (SATB2)-associated syndrome (SAS) is a rare syndromic disease associated with a wide variety of phenotypes, including intellectual disability and craniofacial defects. Among them, dental anomalies are the most frequently observed phenotype and thus becomes an important diagnostic criterion for SAS. In this report, we demonstrate three Japanese cases of genetically diagnosed SAS with detailed craniofacial phenotypes. The cases showed multiple dental problems, which have been previously reported to be linked to SAS, including abnormal crown morphologies and pulp stones. One case showed a characteristic enamel pearl at the root furcation. These phenotypes add new insights for differentiating SAS from other disorders.
Subject(s)
Intellectual Disability , Matrix Attachment Region Binding Proteins , Humans , East Asian People , Syndrome , Phenotype , Intellectual Disability/diagnosis , Intellectual Disability/genetics , Matrix Attachment Region Binding Proteins/genetics , Transcription Factors/geneticsABSTRACT
Estimation of dynamic change of crossbridge formation in living cardiomyocytes is expected to provide crucial information for elucidating cardiomyopathy mechanisms, efficacy of an intervention, and others. Here, we established an assay system to dynamically measure second harmonic generation (SHG) anisotropy derived from myosin filaments depended on their crossbridge status in pulsating cardiomyocytes. Experiments utilizing an inheritable mutation that induces excessive myosin-actin interactions revealed that the correlation between sarcomere length and SHG anisotropy represents crossbridge formation ratio during pulsation. Furthermore, the present method found that ultraviolet irradiation induced an increased population of attached crossbridges that lost the force-generating ability upon myocardial differentiation. Taking an advantage of infrared two-photon excitation in SHG microscopy, myocardial dysfunction could be intravitally evaluated in a Drosophila disease model. Thus, we successfully demonstrated the applicability and effectiveness of the present method to evaluate the actomyosin activity of a drug or genetic defect on cardiomyocytes. Because genomic inspection alone may not catch the risk of cardiomyopathy in some cases, our study demonstrated herein would be of help in the risk assessment of future heart failure.
Subject(s)
Myocytes, Cardiac , Second Harmonic Generation Microscopy , Myosins , Actomyosin , MyocardiumABSTRACT
Background Differences in the clinical course of heritable thoracic aortic disease based on the disease-causing gene have not been fully evaluated. To clarify the clinical relevance of causative genes in heritable thoracic aortic disease, we assessed the clinical course of patients categorized based on genetic diagnosis. Methods and Results We investigated cardiovascular events and mortality in 518 genetically diagnosed patients in 4 groups: Group 1, FBN1 (n=344); Group 2, TGFBR1, TGFBR2, SMAD3, or TGFB2 (n=74); Group 3, COL3A1 (n=60); and Group 4, ACTA2 or MYH11 (n=40). The median age at the first cardiovascular event ranged from 30.0 to 35.5 years (P=0.36). Patients with gene variants related to transforming growth factor-ß signaling had a significantly higher rate of subsequent events than those with FBN1 variants (adjusted hazard ratio, 2.33 [95% CI, 1.60-3.38]; P<0.001). Regarding the incidence of aortic dissection, there were no significant differences among the 4 groups in male patients (36.3%, 34.3%, 21.4%, and 54.2%, respectively; P=0.06). Female patients with COL3A1 variants had a significantly lower incidence than female patients in the other 3 groups (34.2%, 59.0%, 3.1%, and 43.8%, respectively; P<0.001). Conclusions Gene variants related to transforming growth factor-ß signaling are associated with a higher incidence of subsequent cardiovascular events than FBN1 variants. COL3A1 variants might be related to a lower incidence of aortic dissection than other gene variants in women only. Identifying the genetic background of patients with heritable thoracic aortic disease is important for determining appropriate treatment.
Subject(s)
Aortic Aneurysm, Thoracic , Aortic Dissection , Humans , Male , Female , Adult , Receptors, Transforming Growth Factor beta/genetics , Aortic Dissection/diagnosis , Aortic Dissection/genetics , Signal Transduction/genetics , Transforming Growth Factors/genetics , Disease Progression , Aortic Aneurysm, Thoracic/diagnosis , Aortic Aneurysm, Thoracic/genetics , MutationABSTRACT
Brachydactyly mental retardation syndrome (BDMR) or chromosome 2q37 deletion syndrome is a genetic disorder caused by 2q37 deletion or haploinsufficiency of histone deacetylase 4 (HDAC4). The HDAC4 gene is responsible for major BDMR phenotypes. The symptoms of BDMR include mild-to-moderate intellectual disability, seizures, autism spectrum disorder, short stature, obesity, and facial dysmorphism. Here, we report a family (n = 5) with BDMR who had a missense variant of HDAC4. Four affected individuals [5-yr-old girl (index case); 15- and 3-yr-old siblings; and father] had mild intellectual disability, three of the four affected individuals had short stature and mild cardiac anomalies, and two of the four affected individuals had hypothyroidism. Whole-exome sequencing and analyses of the index case and her family revealed an allelic variant in the HDAC4 gene (NM_001378414.1:c.2204G>A:p. Arg735Gln). A healthy family member (mother) did not have the missense variant. To our knowledge, this is the first report of a missense variation in HDAC4 that is associated with BDMR.
ABSTRACT
The MYH7 R453 variant has been identified in inherited hypertrophic cardiomyopathy (HCM) and is associated with sudden death and a poor prognosis. The detailed clinical course of HCM with the MYH7 R453 variant, from a preserved to a reduced left ventricular ejection fraction, has not been reported. We identified the MYH7 R453C and R453H variants in three patients who progressively developed advanced heart failure requiring circulatory support and summarized the clinical course and echocardiographic parameters of these patients over the years. Because of the rapid disease progression, we consider genetic screening for patients with HCM imperative for future prognosis stratification.
Subject(s)
Cardiomyopathy, Hypertrophic , Heart Failure , Humans , Mutation/genetics , Stroke Volume , Ventricular Function, Left , Cardiomyopathy, Hypertrophic/complications , Cardiomyopathy, Hypertrophic/genetics , Heart Failure/genetics , Disease Progression , Myosin Heavy Chains/genetics , Cardiac Myosins/geneticsABSTRACT
Intellectual developmental disorder with dysmorphic facies, speech delay, and T-cell abnormalities (MIM # 618092) is a congenital disorder derived from pathogenic variants of the B-cell leukemia/lymphoma 11B gene (BCL11B). Several variants have been reported to date. Here, through comprehensive genomic analysis, a novel BCL11B truncation variant, NM_138576.4(BCL11B_v001): c.2439_2452dup [p.(His818Argfs*31)], was identified in a Japanese male patient with developmental delay, distinctive features, and early craniosynostosis.
ABSTRACT
Background: The aim of the trial is to evaluate the effectiveness of interventions provided by online support program apps, adopting health-related quality of life (HR-QOL) scores as indicators. Methods: The design is as an open, randomized, parallel-group trial with longitudinal data collection. The subjects will be female cancer patients receiving treatment in a Japanese National Cancer Hospital. Patients assigned to the experimental group will use three apps: an app for them to monitor their own health (monitoring app), an app to assess their understanding of their diagnosis and treatment and their readiness to receive treatment (confirmation app), and an app to address mental health issues (writing app); patients assigned to the control group will use only the monitoring app. At baseline (before patients undergo cancer treatment) and three other times during the study, evaluation indicators will be obtained from three different standardized HR-QOL scales that are incorporated in the monitoring app. The study hypothesis is that at 6 months after patients' baseline health monitoring, patients in the experimental group will have improved HR-QOL as compared with patients in the control group. Conclusion: This study is based on self-regulation theory, so it is important that the online support program works in an efficient way with respect to patients finding and setting their own health-related goals and adapting their behaviors to achieve those goals. Verifying the effectiveness of the combination of the three apps will show that it is a scientifically valid approach to maintaining or improving the HR-QOL of cancer patients.
ABSTRACT
Coffin-Siris syndrome (CSS) is a congenital disorder that is characterized by an absent/hypoplastic fifth distal phalanx, psychomotor developmental delay, and coarse facial features. One of the causative genes, ARID1B (AT-rich interactive domain-containing protein 1B), encodes components of the BAF chromatin remodeling complexes. Here, we report a case of a 3-year 8-month-old male with a novel nonsense variant (NM_001374820.1:c.4282C > T, p.(Gln1428*)) in the ARID1B gene, which was identified with whole-exome sequencing. He showed clinical symptoms of cleft soft palate, distinctive facial features (flat nasal bridge, thick eyebrows, and long eyelashes), right cryptorchidism, and hypertrichosis that partially overlapped with CSS. One of the most characteristic features of CSS is absent/hypoplastic fifth distal phalanx. He showed no obvious clinical finding in the lengths of his fingers or in the formation of his fingernails. However, radiographic analyses of the metacarpophalangeal bones revealed shortening of all the distal phalanges and fifth middle phalanges, suggesting brachydactyly. We performed mRNA analyses and revealed that both nonsense-mediated decay and nonsense-associated altered splicing were simultaneously caused by the c.4282C > T nonsense variant. The proband's clinical manifestations fit the previously reported criteria of disease for CSS or intellectual disability with ARID1B variant. Altogether, we suggest that c.4282C > T is a pathogenic variant that causes this clinical phenotype.