Publications by authors named "Yonehiro Kanemura"

140 Publications

Phosphorylation of GAP-43 T172 is a molecular marker of growing axons in a wide range of mammals including primates.

Mol Brain 2021 04 8;14(1):66. Epub 2021 Apr 8.

Departments of Neurochemistry and Molecular Cell Biology, School of Medicine and Graduate School of Medical/Dental Sciences, Niigata University, Niigata, 951-8510, Japan.

GAP-43 is a vertebrate neuron-specific protein and that is strongly related to axon growth and regeneration; thus, this protein has been utilized as a classical molecular marker of these events and growth cones. Although GAP-43 was biochemically characterized more than a quarter century ago, how this protein is related to these events is still not clear. Recently, we identified many phosphorylation sites in the growth cone membrane proteins of rodent brains. Two phosphorylation sites of GAP-43, S96 and T172, were found within the top 10 hit sites among all proteins. S96 has already been characterized (Kawasaki et al., 2018), and here, phosphorylation of T172 was characterized. In vitro (cultured neurons) and in vivo, an antibody specific to phosphorylated T172 (pT172 antibody) specifically recognized cultured growth cones and growing axons in developing mouse neurons, respectively. Immunoblotting showed that pT172 antigens were more rapidly downregulated throughout development than those of pS96 antibody. From the primary structure, this phosphorylation site was predicted to be conserved in a wide range of animals including primates. In the developing marmoset brainstem and in differentiated neurons derived from human induced pluripotent stem cells, immunoreactivity with pT172 antibody revealed patterns similar to those in mice. pT172 antibody also labeled regenerating axons following sciatic nerve injury. Taken together, the T172 residue is widely conserved in a wide range of mammals including primates, and pT172 is a new candidate molecular marker for growing axons.
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http://dx.doi.org/10.1186/s13041-021-00755-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034164PMC
April 2021

Fine-Tuning Approach for Segmentation of Gliomas in Brain Magnetic Resonance Images with a Machine Learning Method to Normalize Image Differences among Facilities.

Cancers (Basel) 2021 Mar 19;13(6). Epub 2021 Mar 19.

Division of Molecular Modification and Cancer Biology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.

Machine learning models for automated magnetic resonance image segmentation may be useful in aiding glioma detection. However, the image differences among facilities cause performance degradation and impede detection. This study proposes a method to solve this issue. We used the data from the Multimodal Brain Tumor Image Segmentation Benchmark (BraTS) and the Japanese cohort (JC) datasets. Three models for tumor segmentation are developed. In our methodology, the BraTS and JC models are trained on the BraTS and JC datasets, respectively, whereas the fine-tuning models are developed from the BraTS model and fine-tuned using the JC dataset. Our results show that the Dice coefficient score of the JC model for the test portion of the JC dataset was 0.779 ± 0.137, whereas that of the BraTS model was lower (0.717 ± 0.207). The mean Dice coefficient score of the fine-tuning model was 0.769 ± 0.138. There was a significant difference between the BraTS and JC models ( < 0.0001) and the BraTS and fine-tuning models ( = 0.002); however, no significant difference between the JC and fine-tuning models ( = 0.673). As our fine-tuning method requires fewer than 20 cases, this method is useful even in a facility where the number of glioma cases is small.
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http://dx.doi.org/10.3390/cancers13061415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003655PMC
March 2021

Dysfunction of the proteoglycan Tsukushi causes hydrocephalus through altered neurogenesis in the subventricular zone in mice.

Sci Transl Med 2021 Mar;13(587)

Department of Developmental Neurobiology, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan.

The lateral ventricle (LV) is flanked by the subventricular zone (SVZ), a neural stem cell (NSC) niche rich in extrinsic growth factors regulating NSC maintenance, proliferation, and neuronal differentiation. Dysregulation of the SVZ niche causes LV expansion, a condition known as hydrocephalus; however, the underlying pathological mechanisms are unclear. We show that deficiency of the proteoglycan Tsukushi (TSK) in ependymal cells at the LV surface and in the cerebrospinal fluid results in hydrocephalus with neurodevelopmental disorder-like symptoms in mice. These symptoms are accompanied by altered differentiation and survival of the NSC lineage, disrupted ependymal structure, and dysregulated Wnt signaling. Multiple TSK variants found in patients with hydrocephalus exhibit reduced physiological activity in mice in vivo and in vitro. Administration of wild-type TSK protein or Wnt antagonists, but not of hydrocephalus-related TSK variants, in the LV of TSK knockout mice prevented hydrocephalus and preserved SVZ neurogenesis. These observations suggest that TSK plays a crucial role as a niche molecule modulating the fate of SVZ NSCs and point to TSK as a candidate for the diagnosis and therapy of hydrocephalus.
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http://dx.doi.org/10.1126/scitranslmed.aay7896DOI Listing
March 2021

Homozygous ADCY5 mutation causes early-onset movement disorder with severe intellectual disability.

Neurol Sci 2021 Mar 11. Epub 2021 Mar 11.

Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan.

Background: Mutations of theADCY5 have been identified in patients with familial dyskinesia, early-onsetautosomal dominant chorea and dystonia, and benign hereditary chorea. Most ofthe ADCY5 mutations are de novo or transmitted in an autosomal dominantfashion. Only two pedigrees are known to show autosomal recessive inheritance.

Objectives: We report twosiblings with severe ID, dystonic movement, and growth failure with unknownetiology.

Methods: We planned a proband-parentapproach using whole exome sequencing.

Results: Homozygous mutationin exon 21 of the ADCY5 (p.R1238W) was identified in the siblings. Althoughtheir parents were heterozygous for the mutation, they were free from clinicalmanifestations.

Conclusions: Our results furtherexpand the phenotype/genotype correlations of the ADCY5-related disorders.Mutations of ADCY5 should be considered in pediatric patients with ID andinvoluntary movement.
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http://dx.doi.org/10.1007/s10072-021-05152-yDOI Listing
March 2021

Topoisomerase IIβ immunoreactivity (IR) co-localizes with neuronal marker-IR but not glial fibrillary acidic protein-IR in GLI3-positive medulloblastomas: an immunohistochemical analysis of 124 medulloblastomas from the Japan Children's Cancer Group.

Brain Tumor Pathol 2021 Apr 11;38(2):109-121. Epub 2021 Mar 11.

Department of Neuropathology, Aichi Medical University, Institute for Medical Science of Aging, Aichi, Japan.

We previously reported observing GLI3 in medulloblastomas expressing neuronal markers (NM) and/or glial fibrillary acidic protein (GFAP). Furthermore, patients with medulloblastomas expressing NM or GFAP tended to show favorable or poor prognosis, respectively. In the present study, we focused on the role of topoisomerase IIβ (TOP2β) as a possible regulator for neuronal differentiation in medulloblastomas and examined the pathological roles of GLI3, NM, GFAP, and TOP2β expressions in a larger population. We divided 124 medulloblastomas into three groups (NM-/GFAP-, NM +/GFAP-, and GFAP +) based on their immunoreactivity (IR) against NM and GFAP. The relationship among GLI3, NM, GFAP, and TOP2β was evaluated using fluorescent immunostaining and a publicly available single-cell RNA sequencing dataset. In total, 87, 30, and 7 medulloblastomas were classified as NM-/GFAP-, NM + /GFAP-, and GFAP +, and showed intermediate, good, and poor prognoses, respectively. GLI3-IR was frequently observed in NM +/GFAP-  and GFAP + , and TOP2β-IR was frequently observed only in NM +/GFAP-  medulloblastomas. In fluorescent immunostaining, TOP2β-IR was mostly co-localized with NeuN-IR but not with GFAP-IR. In single-cell RNA sequencing, TOP2β expression was elevated in CMAS/DCX-positive, but not in GFAP-positive, cells. NM-IR and GFAP-IR are important for estimating the prognosis of patients with medulloblastoma; hence they should be assessed in clinical practice.
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http://dx.doi.org/10.1007/s10014-021-00396-0DOI Listing
April 2021

CD44 expression in the tumor periphery predicts the responsiveness to bevacizumab in the treatment of recurrent glioblastoma.

Cancer Med 2021 Mar 5;10(6):2013-2025. Epub 2021 Feb 5.

Department of Neurosurgery, Ehime University School of Medicine, Toon, Japan.

Antiangiogenic therapy with bevacizumab (Bev), a monoclonal antibody targeting vascular endothelial growth factor (VEGF), is a common treatment for recurrent glioblastoma (GBM), but its survival benefit is limited. Resistance to Bev is thought to be a major cause of ineffectiveness on Bev therapy. To optimize Bev therapy, identification of a predictive biomarker for responsiveness to Bev is required. Based on our previous study, we focused on the expression and functions of CD44 and VEGF in the Bev therapy. Here, we analyze a relationship between CD44 expression and responsiveness to Bev and elucidate the role of CD44 in anti-VEGF therapy. CD44 and VEGF expression in the tumor core and periphery of 22 GBMs was examined, and the relationship between expression of these molecules and progression-free time on Bev therapy was analyzed. The degree of CD44 expression in the tumor periphery was evaluated by the ratio of the mRNA expression in the tumor periphery to that in the tumor core (P/C ratio). VEGF expression was evaluated by the amount of the mRNA expression in the tumor periphery. To elucidate the roles of CD44 in the Bev therapy, in vitro and in vivo studies were performed using glioma stem-like cells (GSCs) and a GSC-transplanted mouse xenograft model, respectively. GBMs expressing high P/C ratio of CD44 were much more refractory to Bev than those expressing low P/C ratio of CD44, and the survival time of the former was much shorter than that of the latter. In vitro inhibition of VEGF with siRNA or Bev-activated CD44 expression and increased invasion of GSCs. Bev showed no antitumor effects in mice transplanted with CD44-overexpressing GSCs. The P/C ratio of CD44 expression may become a useful biomarker predicting responsiveness to Bev in GBM. CD44 reduces the antitumor effect of Bev, resulting in much more highly invasive tumors.
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http://dx.doi.org/10.1002/cam4.3767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957167PMC
March 2021

Impact of Inversion Time for FLAIR Acquisition on the T2-FLAIR Mismatch Detectability for -Mutant, Non-CODEL Astrocytomas.

Front Oncol 2020 14;10:596448. Epub 2021 Jan 14.

Department of Neurosurgery, Osaka University Graduate School of Medicine, Suita, Japan.

The current research tested the hypothesis that inversion time (TI) shorter than 2,400 ms under 3T for FLAIR can improve the diagnostic accuracy of the T2-FLAIR mismatch sign for identifying mt, non-CODEL astrocytomas. We prepared three different cohorts; 94 MRI from 76 mt, non-CODEL Lower-grade gliomas (LrGGs), 33 MRI from 31 LrGG under the restriction of FLAIR being acquired with TI < 2,400 ms for 3T or 2,016 ms for 1.5T, and 112 MRI from 112 patients from the TCIA/TCGA dataset for LrGG. The presence or absence of the "T2-FLAIR mismatch sign" was evaluated, and we compared diagnostic accuracies according to TI used for FLAIR acquisition. The T2-FLAIR mismatch sign was more frequently positive when TI was shorter than 2,400 ms under 3T for FLAIR acquisition ( = 0.0009, Fisher's exact test). The T2-FLAIR mismatch sign was positive only for mt, non-CODEL astrocytomas even if we confined the cohort with FLAIR acquired with shorter TI ( = 0.0001, Fisher's exact test). TCIA/TCGA dataset validated that the sensitivity, specificity, PPV, and NPV of the T2-FLAIR mismatch sign to identify mt, non-CODEL astrocytomas improved from 31, 90, 79, and 51% to 67, 94, 92, and 74%, respectively and the area under the curve of ROC improved from 0.63 to 0.87 when FLAIR was acquired with shorter TI. We revealed that TI for FLAIR impacts the T2-FLAIR mismatch sign's diagnostic accuracy and that FLAIR scanned with TI < 2,400 ms in 3T is necessary for LrGG imaging.
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http://dx.doi.org/10.3389/fonc.2020.596448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841010PMC
January 2021

Diagnostic Performance of [C]Methionine Positron Emission Tomography in Newly Diagnosed and Untreated Glioma Based on the Revised World Health Organization 2016 Classification.

World Neurosurg 2021 Apr 11;148:e471-e481. Epub 2021 Jan 11.

Department of Neurosurgery, Osaka City University Graduate School of Medicine, Osaka, Japan.

Background: The relationship between uptake of amino acid tracer with positron emission tomography (PET) and glioma subtypes/gene status is still unclear.

Objective: To assess the relationship between uptake of [C]methionine using PET and pathology, IDH (isocitrate dehydrogenase) mutation, 1p/19q codeletion, and TERT (telomerase reverse transcriptase) promoter status in gliomas.

Methods: The participants were 68 patients with newly diagnosed and untreated glioma who underwent surgical excision and preoperative [C]methionine PET examination at Osaka City University Hospital between July 2011 and March 2018. Clinical and imaging studies were reviewed retrospectively based on the medical records at our institution.

Results: The mean lesion/contralateral normal brain tissue (L/N) ratio of diffuse astrocytomas was significantly lower than that of anaplastic astrocytomas (P = 0.00155), glioblastoma (P < 0.001), and oligodendrogliomas (P = 0.0157). The mean L/N ratio of IDH mutant gliomas was significantly lower than that of IDH wild-type gliomas (median 1.75 vs. 2.61; P = 0.00162). A mean L/N ratio of 2.05 provided the best sensitivity and specificity for distinguishing between IDH mutant and IDH wild-type gliomas (69.2% and 76.2%, respectively). The mean L/N ratio of TERT promoter mutant gliomas was significantly higher than that of TERT promoter wild-type gliomas (P = 0.0147). Multiple regression analysis showed that pathologic diagnosis was the only influential factor on L/N ratio.

Conclusions: Distinguishing glioma subtypes based on the revised 2016 World Health Organization classification of the central nervous system tumors on the basis of [C]methionine PET alone seems to be difficult. However, [C]methionine PET might be useful for predicting the IDH mutation status in newly diagnosed and untreated gliomas noninvasively before tumor resection.
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http://dx.doi.org/10.1016/j.wneu.2021.01.012DOI Listing
April 2021

HDACs and MYC in medulloblastoma: how do HDAC inhibitors control MYC-amplified tumors?

Neuro Oncol 2021 02;23(2):173-174

Department of Biomedical Research and Innovation, Institute for Clinical Research, National Hospital Organization Osaka National Hospital, Osaka, Japan.

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http://dx.doi.org/10.1093/neuonc/noaa292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906052PMC
February 2021

Alpha-synuclein dynamics in induced pluripotent stem cell-derived dopaminergic neurons from a Parkinson's disease patient (PARK4) with SNCA triplication.

FEBS Open Bio 2021 Feb 5;11(2):354-366. Epub 2021 Jan 5.

Division of Regenerative Medicine, Department of Biomedical Research and Innovation, Institute for Clinical Research, National Hospital Organization Osaka National Hospital, Japan.

Parkinson's disease (PD) is a neurodegenerative disorder caused by the selective loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc). Lewy bodies (LBs), another histological hallmark of PD, are observed in patients with familial or sporadic PD. The therapeutic potential of reducing the accumulation of α-synuclein, a major LB component, has been investigated, but it remains unknown whether the formation of LBs results in the loss of DA neurons. PARK4 patients exhibit multiplication of the α-synuclein gene (SNCA) without any pathological mutations, but their symptoms develop relatively early. Therefore, study of PARK4 might help elucidate the mechanism of α-synuclein aggregation. In this study, we investigated the dynamics of α-synuclein during the early stage of immature DA neurons, which were differentiated from human-induced pluripotent stem cells (hiPSCs) derived from either a PARK4 patient with SNCA triplication or a healthy donor. We observed increased α-synuclein accumulation in PARK4 hiPSC-derived DA neurons relative to those derived from healthy donor hiPSCs. Interestingly, α-synuclein accumulation disappeared over time in the PARK4 patient-derived DA neurons. Moreover, an SNCA-specific antisense oligonucleotide could reduce α-synuclein levels during the accumulation stage. These observations may help reveal the mechanisms that regulate α-synuclein levels, which may consequently be useful in the development of new therapies for patients with sporadic or familial PD.
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http://dx.doi.org/10.1002/2211-5463.13060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876504PMC
February 2021

Activated leukocyte cell adhesion molecule expression correlates with the WNT subgroup in medulloblastoma and is involved in regulating tumor cell proliferation and invasion.

PLoS One 2020 3;15(12):e0243272. Epub 2020 Dec 3.

Department of Neurosurgery, Osaka University Graduate School of Medicine, Osaka, Japan.

Cluster of differentiation (CD) 166 or activated leukocyte cell adhesion molecule (ALCAM) is a transmembrane molecule known to be an intercellular adhesion factor. The expression and function of ALCAM in medulloblastoma (MB), a pediatric brain tumor with highly advanced molecular genetics, remains unclear. Therefore, this study aimed to clarify the significance and functional role of ALCAM expression in MB. ALCAM expression in 45 patients with MB was evaluated by immunohistochemical analysis of formalin-fixed paraffin-embedded clinical specimens and the relationship between ALCAM expression and pathological type/molecular subgroup, such as WNT, SHH, Group 3, and Group 4, was examined. Eight ALCAM positive (18%), seven partially positive (16%), and 30 negative (67%) cases were detected. All seven cases of the WNT molecular subgroup were ALCAM positive and ALCAM expression strongly correlated with this subgroup (P < 0.0001). In addition, functional studies using MB cell lines revealed ALCAM expression affected proliferation and migration as a positive regulator in vitro. However, ALCAM silencing did not affect survival or the formation of leptomeningeal dissemination in an orthotopic mouse model, but did induce a malignant phenotype with increased tumor cell invasion at the dissemination sites (P = 0.0029). In conclusion, our results revealed that ALCAM exhibited highly specific expression in the WNT subgroup of MB. Furthermore, we demonstrated that the cell kinetics of MB cell lines can be altered by the expression of ALCAM.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243272PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7714159PMC
January 2021

TERT promoter mutation confers favorable prognosis regardless of 1p/19q status in adult diffuse gliomas with IDH1/2 mutations.

Acta Neuropathol Commun 2020 11 23;8(1):201. Epub 2020 Nov 23.

Department of Neurosurgery, Dokkyo Medical University, 880, Kitakobayashi, Mibu-City, Tochigi, 321-0293, Japan.

TERT promoter mutations are commonly associated with 1p/19q codeletion in IDH-mutated gliomas. However, whether these mutations have an impact on patient survival independent of 1p/19q codeletion is unknown. In this study, we investigated the impact of TERT promoter mutations on survival in IDH-mutated glioma cases. Detailed clinical information and molecular status data were collected for a cohort of 560 adult patients with IDH-mutated gliomas. Among these patients, 279 had both TERT promoter mutation and 1p/19q codeletion, while 30 had either TERT promoter mutation (n = 24) or 1p/19q codeletion (n = 6) alone. A univariable Cox proportional hazard analysis for survival using clinical and genetic factors indicated that a Karnofsky performance status score (KPS) of 90 or 100, WHO grade II or III, TERT promoter mutation, 1p/19q codeletion, radiation therapy, and extent of resection (90-100%) were associated with favorable prognosis (p < 0.05). A multivariable Cox regression model revealed that TERT promoter mutation had a significantly favorable prognostic impact (hazard ratio = 0.421, p = 0.049), while 1p/19q codeletion did not have a significant impact (hazard ratio = 0.648, p = 0.349). Analyses incorporating patient clinical and genetic information were further conducted to identify subgroups showing the favorable prognostic impact of TERT promoter mutation. Among the grade II-III glioma patients with a KPS score of 90 or 100, those with IDH-TERT co-mutation and intact 1p/19q (n = 17) showed significantly longer survival than those with IDH mutation, wild-type TERT, and intact 1p/19q (n = 185) (5-year overall survival, 94% and 77%, respectively; p = 0.032). Our results demonstrate that TERT promoter mutation predicts favorable prognosis independent of 1p/19q codeletion in IDH-mutated gliomas. Combined with its adverse effect on survival among IDH-wild glioma cases, the bivalent prognostic impact of TERT promoter mutation may help further refine the molecular diagnosis and prognostication of diffuse gliomas.
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http://dx.doi.org/10.1186/s40478-020-01078-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685625PMC
November 2020

promoter mutation associated with multifocal phenotype and poor prognosis in patients with wild-type glioblastoma.

Neurooncol Adv 2020 Jan-Dec;2(1):vdaa114. Epub 2020 Sep 1.

Department of Neurosurgery, Faculty of Medicine, Yamagata University, Yamagata City, Yamagata, Japan.

Background: Although mutations in the promoter region of the telomerase reverse transcriptase (p) gene are the most common alterations in glioblastoma (GBM), their clinical significance remains unclear. Therefore, we investigated the impact of p status on patient outcome and clinicopathological features in patients with GBM over a long period of follow-up.

Methods: We retrospectively analyzed 153 cases of GBM. Six patients with isocitrate dehydrogenase 1 () or gene mutations were excluded from this study. Among the 147 cases of wild-type GBM, 92 (62.6%) had the p mutation. Clinical, immunohistochemical, and genetic factors (, gene mutation, CD133, ATRX expression, -methylguanine-DNA methyltransferase [] promoter methylation) and copy number alterations (CNAs) were investigated.

Results: GBM patients with the p mutation were older at first diagnosis versus those with p wild type (66.0 vs. 60.0 years, respectively, = .034), and had shorter progression-free survival (7 vs. 10 months, respectively, = .015) and overall survival (16 vs. 24 months, respectively, = .017). Notably, magnetic resonance imaging performed showed that p-mutant GBM was strongly associated with multifocal/distant lesions ( = .004). According to the CNA analysis, p mutations were positively correlated with amp/gain, deletion, and deletion; however, these mutations were negatively correlated with amp/gain, gain, and deletion.

Conclusions: p mutations were strongly correlated with multifocal/distant lesions and poor prognosis in patients with wild-type GBM. Less aggressive GBM with p wild type may be a distinct clinical and molecular subtype of wild-type GBM.
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http://dx.doi.org/10.1093/noajnl/vdaa114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586143PMC
September 2020

Surgical Treatment of Brain Metastasis of Extramammary Paget's Disease: A Case Report.

NMC Case Rep J 2020 Sep 17;7(4):189-193. Epub 2020 Sep 17.

Department of Neurosurgery, Osaka National Hospital, National Hospital Organization, Osaka, Osaka, Japan.

Extramammary Paget's disease (EMPD) is a rare form of neoplasm. Metastasis of EMPD to locations other than lymph nodes and intra-epithelial regions is rare; there are a limited number of case reports of metastases to the liver, lung, bone, and brain. We present a rare case of EMPD that metastasized to the brain and was treated with surgical resection. A 66-year-old man presented with a small palpable mass in the scrotum. After 5 years of observation, he was diagnosed with EMPD that metastasized to the lymph nodes and lung. Tumor resection and postoperative chemotherapy were performed. Six months after the last chemotherapy treatment, he presented with a right temporal lobe tumor and underwent surgical resection. Histopathological analysis revealed brain metastasis of EMPD. Three months after surgery, magnetic resonance imaging (MRI) showed local tumor recurrence, and intensity modulated radiation therapy (IMRT) (45 Gy/15 Fr) was performed. Although the metastatic brain tumor was well controlled, the primary tumor progressed. He was provided best supportive care and died 5 months after brain tumor resection. In this report, we present a rare case of brain metastasis of EMPD, treated with surgical resection, and histopathologically confirmed to be metastatic EMPD.
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http://dx.doi.org/10.2176/nmccrj.cr.2019-0292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538455PMC
September 2020

Prenatal clinical manifestations in individuals with variants.

J Med Genet 2020 Jul 30. Epub 2020 Jul 30.

Department of Pediatric Neurology, Bobath Memorial Hospital, Osaka, Osaka, Japan.

Background: Variants in the type IV collagen gene () cause early-onset cerebrovascular diseases. Most individuals are diagnosed postnatally, and the prenatal features of individuals with variants remain unclear.

Methods: We examined in 218 individuals with suspected /2-related brain defects. Among those arising from variants, we focused on individuals showing prenatal abnormal ultrasound findings and validated their prenatal and postnatal clinical features in detail.

Results: Pathogenic variants were detected in 56 individuals (n=56/218, 25.7%) showing porencephaly (n=29), schizencephaly (n=12) and others (n=15). Thirty-four variants occurred de novo (n=34/56, 60.7%). Foetal information was available in 47 of 56 individuals, 32 of whom (n=32/47, 68.1%) had one or more foetal abnormalities. The median gestational age at the detection of initial prenatal abnormal features was 31 weeks of gestation. Only 14 individuals had specific prenatal findings that were strongly suggestive of features associated with variants. Foetal ventriculomegaly was the most common initial feature (n=20/32, 62.5%). Posterior fossa abnormalities, including Dandy-Walker malformation, were observed prenatally in four individuals. Regarding extrabrain features, foetal growth restriction was present in 16 individuals, including eight individuals with comorbid ventriculomegaly.

Conclusions: Prenatal observation of ventriculomegaly with comorbid foetal growth restriction should prompt a thorough ultrasound examination and gene testing should be considered when pathogenic variants are strongly suspected.
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http://dx.doi.org/10.1136/jmedgenet-2020-106896DOI Listing
July 2020

A case of medulloblastoma in a patient with fetal ventricular enlargement.

Childs Nerv Syst 2021 Mar 18;37(3):977-982. Epub 2020 Jun 18.

Department of Neurosurgery, Kansai Medical University, 2-5-1 Shinmachi, Hirakata City, Osaka, 573-1010, Japan.

Medulloblastoma is the second-most common malignant tumor in children. Medulloblastoma has been categorized into four distinct molecular subgroups: WNT, sonic hedgehog (SHH), group 3, and group 4. We report on a male child with medulloblastoma, in whom an enlarged ventricle was diagnosed in utero. Magnetic resonance imaging showed cyst formation in the cerebellar hemisphere initially, with tumor growth being indicated later. Tumor resection was performed when the boy was 12 months old. The histological findings showed extensive nodularity. Further genetic analysis revealed the tumor to be SHH type. This is the first description of a medulloblastoma observed from the fetal stage. Our findings in this case indicate that cyst formation may be the pre-neoplastic lesion of SHH-subtype medulloblastomas.
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http://dx.doi.org/10.1007/s00381-020-04725-0DOI Listing
March 2021

Molecular characteristics and clinical outcomes of elderly patients with IDH-wildtype glioblastomas: comparative study of older and younger cases in Kansai Network cohort.

Brain Tumor Pathol 2020 Apr 2;37(2):50-59. Epub 2020 May 2.

Kansai Molecular Diagnosis Network for CNS Tumors, Osaka, 540-0006, Japan.

Aging is a known negative prognostic factor in glioblastomas (GBM). Whether particular genetic backgrounds are a factor in poor outcomes of elderly patients with GBM warrants investigation. We aim to elucidate any differences between older and younger adult patients with IDH-wildtype GBM regarding both molecular characteristics and clinical outcomes. We collected adult cases diagnosed with IDH-wildtype GBM from the Kansai Network. Clinical and pathological characteristics were analyzed retrospectively and compared between older (≥ 70 years) and younger (≤ 50 years) cases. Included were 92 older vs. 33 younger cases. The older group included more patients with preoperative Karnofsky performance status score < 70 and had a shorter survival time than the younger group. MGMT promoter was methylated more frequently in the older group. TERT promoter mutation was more common in the older group. There were significant differences in DNA copy-number alteration profiles between age groups in PTEN deletion and CDK4 amplification/gain. In the older group, no molecular markers were identified, but surgical resection was an independent prognostic factor. Age-specific survival difference was significant in the MGMT methylated and TERT wildtype subgroup. Elderly patients have several potential factors in poor prognosis of glioblastomas. Varying molecular profiles may explain differing rates of survival between generations.
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http://dx.doi.org/10.1007/s10014-020-00363-1DOI Listing
April 2020

Infantile macrocephaly and multiple subcutaneous lipomas diagnosed with hamartoma tumor syndrome: A case report.

Mol Clin Oncol 2020 Apr 27;12(4):329-335. Epub 2020 Jan 27.

Department of Genetic Medicine, Takatsuki General Hospital, Takatsuki, Osaka 569-1192, Japan.

A heterozygous loss-of-function mutation of the gene, one of the tumor suppressor genes, causes a wide variety of disorders, ranging from macrocephaly/autism syndrome to hamartoma tumor syndrome, including Cowden disease that causes thyroid and breast cancer mainly in the adolescence and young adult generation. An 8-month-old male infant with simple macrocephaly developed a café-au-lait spot and two subcutaneous tumors at the age of 1 year. One of the tumors developed rapidly was resected at the age of 1 year and 9 months and identified as benign lipoma. From the age of 2 years, the patient often threw a tantrum. At the age of 2 years and 9 months, a pathogenic germline mutation was identified in the gene (NM_000314.7), c.195C>A, p.Y65 in the form of a heterozygous germline variant. Developmental delay was noted but no tumors were found in the thyroid gland and breasts. Immunohistochemistry for PTEN in the resected lipoma demonstrated that the PTEN expression pattern was similar to that in a subcutaneous adipose tissue from a normal subject, suggesting that two-hit was not likely involved in the rapid growth of this lipoma. At the age of 5 years, the patient was diagnosed with autism spectrum disorders with moderate developmental delay. A long-term follow-up is underway to examine developmental changes in psychomotor disorders and possible tumor formation.
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http://dx.doi.org/10.3892/mco.2020.1988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058917PMC
April 2020

T-FLAIR Mismatch Sign Is Caused by Long T and T of IDH-mutant, 1p19q Non-codeleted Astrocytoma.

Magn Reson Med Sci 2021 Mar 27;20(1):119-123. Epub 2020 Feb 27.

Department of Diagnostic and Interventional Radiology, Osaka International Cancer Institute.

T-fluid-attenuated inversion recovery images (FLAIR) mismatch sign is now known to be a specific yet insensitive image feature for IDH-mutant, 1p19q non-codeleted astrocytoma. The current study revealed that lesion presenting T-FLAIR mismatch exhibited extremely long T- and T-relaxation time while T-FLAIR matched lesions showed low to moderate values. On the other hand, IDH-wildtype tumors presented noticeably short T- and T-relaxation time. These different relaxation time characteristics seemed to render T-FLAIR mismatch sign of becoming such a unique and specific image feature for IDH-mutant, 1p19q non-codeleted astrocytoma.
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http://dx.doi.org/10.2463/mrms.bc.2019-0196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952199PMC
March 2021

A 21-Month-Old Boy with One-Month History of Vomiting.

Brain Pathol 2020 03;30(2):425-426

Department of Hematology/Oncology, Saitama Children's Medical Center, Saitama, Japan.

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http://dx.doi.org/10.1111/bpa.12823DOI Listing
March 2020

Relationships between recurrence patterns and subventricular zone involvement or CD133 expression in glioblastoma.

J Neurooncol 2020 Feb 4;146(3):489-499. Epub 2020 Feb 4.

Department of Neurosurgery, Faculty of Medicine, Yamagata University, 2-2 Iida-Nishi, Yamagata, Yamagata, 990-9585, Japan.

Introduction: We previously reported that CD133 expression correlated with the recurrence pattern of glioblastoma (GBM). Subventricular zone (SVZ) involvement may also be associated with distant recurrence in GBM. Therefore, we herein investigated whether the combined analysis of SVZ involvement and CD133 expression is useful for predicting the pattern of GBM recurrence.

Materials And Methods: We retrospectively analyzed 167 cases of GBM. Tumors were divided into four groups based on spatial relationships between contrast-enhanced lesions (CEL) and the SVZ or cortex (Ctx) on MRI. The initial recurrence pattern (local/distant) was obtained from medical records. To identify factors predictive of recurrence, we examined CD133 expression by immunohistochemical, clinical (age, sex, KPS, Ki-67 labeling index, surgery, and MRI characteristics), and genetic (IDH1, MGMT, and BRAF) factors.

Results: The CD133 expression rate was higher in SVZ-positive tumors than in SVZ-negative tumors (P = 0.046). Distant recurrence was observed in 21% of patients, and no significant difference was noted in recurrence patterns among the four groups. However, strong CD133 expression was associated with a shorter time to distant recurrence in univariate, multivariate, and propensity-matched scoring analyses (P < 0.0001, P = 0.001, and P = 0.0084, respectively). In the combined analysis, distant recurrence was the most frequent (70%) in group III (SVZ-negative, Ctx-positive) GBM and those with high CD133 expression rates (≥ 15%).

Conclusion: An integrated analysis of CD133 expression and MRI-based tumor classification may be useful for predicting the recurrence pattern of GBM.
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http://dx.doi.org/10.1007/s11060-019-03381-yDOI Listing
February 2020

Prediction of IDH and TERT promoter mutations in low-grade glioma from magnetic resonance images using a convolutional neural network.

Sci Rep 2019 12 30;9(1):20311. Epub 2019 Dec 30.

Department of Neurosurgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.

Identification of genotypes is crucial for treatment of glioma. Here, we developed a method to predict tumor genotypes using a pretrained convolutional neural network (CNN) from magnetic resonance (MR) images and compared the accuracy to that of a diagnosis based on conventional radiomic features and patient age. Multisite preoperative MR images of 164 patients with grade II/III glioma were grouped by IDH and TERT promoter (pTERT) mutations as follows: (1) IDH wild type, (2) IDH and pTERT co-mutations, (3) IDH mutant and pTERT wild type. We applied a CNN (AlexNet) to four types of MR sequence and obtained the CNN texture features to classify the groups with a linear support vector machine. The classification was also performed using conventional radiomic features and/or patient age. Using all features, we succeeded in classifying patients with an accuracy of 63.1%, which was significantly higher than the accuracy obtained from using either the radiomic features or patient age alone. In particular, prediction of the pTERT mutation was significantly improved by the CNN texture features. In conclusion, the pretrained CNN texture features capture the information of IDH and TERT genotypes in grade II/III gliomas better than the conventional radiomic features.
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http://dx.doi.org/10.1038/s41598-019-56767-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937237PMC
December 2019

Radiomics and MGMT promoter methylation for prognostication of newly diagnosed glioblastoma.

Sci Rep 2019 10 8;9(1):14435. Epub 2019 Oct 8.

Kansai Molecular Diagnosis Network for CNS Tumors, Osaka, 540-0006, Japan.

We attempted to establish a magnetic resonance imaging (MRI)-based radiomic model for stratifying prognostic subgroups of newly diagnosed glioblastoma (GBM) patients and predicting O (6)-methylguanine-DNA methyltransferase promotor methylation (pMGMT-met) status of the tumor. Preoperative MRI scans from 201 newly diagnosed GBM patients were included in this study. A total of 489 texture features including the first-order feature, second-order features from 162 datasets, and location data from 182 datasets were collected. Supervised principal component analysis was used for prognostication and predictive modeling for pMGMT-met status was performed based on least absolute shrinkage and selection operator regression. 22 radiomic features that were correlated with prognosis were used to successfully stratify patients into high-risk and low-risk groups (p = 0.004, Log-rank test). The radiomic high- and low-risk stratification and pMGMT status were independent prognostic factors. As a matter of fact, predictive accuracy of the pMGMT methylation status was 67% when modeled by two significant radiomic features. A significant survival difference was observed among the combined high-risk group, combined intermediate-risk group (this group consists of radiomic low risk and pMGMT-unmet or radiomic high risk and pMGMT-met), and combined low-risk group (p = 0.0003, Log-rank test). Radiomics can be used to build a prognostic score for stratifying high- and low-risk GBM, which was an independent prognostic factor from pMGMT methylation status. On the other hand, predictive accuracy of the pMGMT methylation status by radiomic analysis was insufficient for practical use.
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http://dx.doi.org/10.1038/s41598-019-50849-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6783410PMC
October 2019

Validation of magnetic resonance imaging-based automatic high-grade glioma segmentation accuracy via C-methionine positron emission tomography.

Oncol Lett 2019 Oct 8;18(4):4074-4081. Epub 2019 Aug 8.

Department of Neurosurgery, Osaka University Graduate School of Medicine, Suita, Osaka 5650871, Japan.

Brain Tumor Image Analysis (BraTumIA) is a fully automated segmentation tool dedicated to detecting brain tumors imaged by magnetic resonance imaging (MRI). BraTumIA has recently been applied to several clinical investigations; however, the validity of this novel method has not yet been fully examined. The present study was conducted to validate the quality of tumor segmentation with BraTumIA in comparison with results from C-methionine positron emission tomography (MET-PET). A total of 45 consecutive newly diagnosed high-grade gliomas imaged by MRI and MET-PET were analyzed. Automatic tumor segmentation was conducted by BraTumIA and the resulting segmentation images were registered to MET-PET. Three-dimensional conformal association between these two modalities was calculated, considering MET-PET as the gold standard. High underestimation and overestimation errors were observed in tumor segmentation calculated by BraTumIA compared with MET-PET. Furthermore, when the tumor/normal ratio threshold was set at 1.3 from MET-PET, the BraTumIA false-positive fraction was ~0.4 and the false-negative fraction was 0.9. By tightening this threshold to 2.0, the BraTumIA false-positive fraction was 0.6 and the false-negative fraction was 0.6. Following comparison of segmentation performance with BraTumIA with regard to glioblastoma (GBM) and World Health Organization (WHO) grade III glioma, GBM exhibited better segmentation compared with WHO grade III glioma. Although BraTumIA may be able to detect enhanced tumors, non-enhancing tumors and necrosis, the spatial concordance rate with MET-PET was relatively low. Careful interpretation is therefore required when using this technique.
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http://dx.doi.org/10.3892/ol.2019.10734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6732988PMC
October 2019

Evaluation of the susceptibility of neurons and neural stem/progenitor cells derived from human induced pluripotent stem cells to anticancer drugs.

J Pharmacol Sci 2019 Aug 21;140(4):331-336. Epub 2019 Aug 21.

Division of Regenerative Medicine, Department of Biomedical Research and Innovation, Institute for Clinical Research, National Hospital Organization Osaka National Hospital, Osaka 540-0006, Japan; Department of Neurosurgery, National Hospital Organization Osaka National Hospital, Osaka 540-0006, Japan; Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan. Electronic address:

Various chemicals, including pharmaceuticals, can induce acute or delayed neurotoxicity in humans. Because isolation of human primary neurons is extremely difficult, toxicity tests for these agents have been performed using in vivo or in vitro models. Human induced pluripotent stem cells (hiPSCs) can be used to establish hiPSC-derived neural stem/progenitor cells (hiPSC-NSPCs), which can then be used to obtain hiPSC-neurons. In this study, we differentiated hiPSC-NSPCs into neurons and evaluated the susceptibility of hiPSC-neurons and parental hiPSC-NSPCs to anticancer drugs in vitro by ATP assay and immunocytostaining. The hiPSC-neurons were more resistant to anticancer drugs than the parental hiPSC-NSPCs. In the toxicity tests, high-dose cisplatin reduced the levels of ELAVL3/4, a neuronal marker, in the hiPSC-neurons. These results suggest that our methodology is potentially applicable for efficient determination of the toxicity of any drug to hiPSC-neurons.
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http://dx.doi.org/10.1016/j.jphs.2019.08.002DOI Listing
August 2019

Integrated clinical, histopathological, and molecular data analysis of 190 central nervous system germ cell tumors from the iGCT Consortium.

Neuro Oncol 2019 12;21(12):1565-1577

Department of Neuro-Oncology/Neurosurgery, Saitama Medical University International Medical Center, Saitama, Japan.

Background: We integrated clinical, histopathological, and molecular data of central nervous system germ cell tumors to provide insights into their management.

Methods: Data from the Intracranial Germ Cell Tumor Genome Analysis (iGCT) Consortium were reviewed. A total of 190 cases were classified as primary germ cell tumors (GCTs) based on central pathological reviews.

Results: All but one of the cases that were bifocal (neurohypophysis and pineal glands) and cases with multiple lesions including neurohypophysis or pineal gland were germinomas (34 of 35). Age was significantly higher in patients with germinoma than other histologies. Comparison between tumor marker and histopathological diagnoses showed that 18.2% of histopathologically diagnosed germinomas were marker positive and 6.1% of non-germinomatous GCTs were marker negative, suggesting a limitation in the utility of markers or histopathology alone using small specimens for diagnosis. Comparison between local and central histopathological diagnoses revealed a discordance of 12.7%. Discordance was significantly less frequent in biopsy cases, implying difficulty in detecting all histopathological components of heterogeneous GCTs. Germinomas at the typical sites (neurohypophysis or pineal gland) showed a better progression-free survival than those at atypical sites (P = 0.03). A molecular clinical association study revealed frequent mitogen-activated protein kinase (MAPK) pathway mutations in males (51.4% vs 14.3%, P = 0.007), and phosphatidylinositol-3 kinase/mammalian target of rapamycin (PI3K/mTOR) pathway mutations in basal ganglia cases (P = 0.004). Basal ganglia cases also had frequent chromosomal losses. Some chromosomal aberrations (2q, 8q gain, 5q, 9p/q, 13q, 15q loss) showed potential prognostic significance.

Conclusions: The in-depth findings of this study regarding clinical and molecular heterogeneity will increase our understanding of the pathogenesis of this enigmatic tumor.
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http://dx.doi.org/10.1093/neuonc/noz139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6917411PMC
December 2019

IMP dehydrogenase-2 drives aberrant nucleolar activity and promotes tumorigenesis in glioblastoma.

Nat Cell Biol 2019 08 1;21(8):1003-1014. Epub 2019 Aug 1.

Division of Human Biology, Solid Tumor and Translational Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

In many cancers, high proliferation rates correlate with elevation of rRNA and tRNA levels, and nucleolar hypertrophy. However, the underlying mechanisms linking increased nucleolar transcription and tumorigenesis are only minimally understood. Here we show that IMP dehydrogenase-2 (IMPDH2), the rate-limiting enzyme for de novo guanine nucleotide biosynthesis, is overexpressed in the highly lethal brain cancer glioblastoma. This leads to increased rRNA and tRNA synthesis, stabilization of the nucleolar GTP-binding protein nucleostemin, and enlarged, malformed nucleoli. Pharmacological or genetic inactivation of IMPDH2 in glioblastoma reverses these effects and inhibits cell proliferation, whereas untransformed glia cells are unaffected by similar IMPDH2 perturbations. Impairment of IMPDH2 activity triggers nucleolar stress and growth arrest of glioblastoma cells even in the absence of functional p53. Our results reveal that upregulation of IMPDH2 is a prerequisite for the occurance of aberrant nucleolar function and increased anabolic processes in glioblastoma, which constitutes a primary event in gliomagenesis.
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http://dx.doi.org/10.1038/s41556-019-0363-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686884PMC
August 2019

Distribution differences in prognostic copy number alteration profiles in IDH-wild-type glioblastoma cause survival discrepancies across cohorts.

Acta Neuropathol Commun 2019 06 18;7(1):99. Epub 2019 Jun 18.

Kansai Molecular Diagnosis Network for CNS Tumors, Osaka-City, Osaka, Japan.

The diagnosis and prognostication of glioblastoma (GBM) remain to be solely dependent on histopathological findings and few molecular markers, despite the clinical heterogeneity in this entity. To address this issue, we investigated the prognostic impact of copy number alterations (CNAs) using two population-based IDH-wild-type GBM cohorts: an original Japanese cohort and a dataset from The Cancer Genome Atlas (TCGA). The molecular disproportions between these cohorts were dissected in light of cohort differences in GBM. The Japanese cohort was collected from cases registered in Kansai Molecular Diagnosis Network for CNS tumors (KNBTG). The somatic landscape around CNAs was analyzed for 212 KNBTG cases and 359 TCGA cases. Next, the clinical impacts of CNA profiles were investigated for 140 KNBTG cases and 152 TCGA cases treated by standard adjuvant therapy using temozolomide-based chemoradiation. The comparative profiling indicated unequal distribution of specific CNAs such as EGFR, CDKN2A, and PTEN among the two cohorts. Especially, the triple overlap CNAs in these loci (triple CNA) were much higher in frequency in TCGA (70.5%) than KNBTG (24.3%), and its prognostic impact was independently validated in both cohorts. The KNBTG cohort significantly showed better prognosis than the TCGA cohort (median overall survival 19.3 vs 15.6 months). This survival difference between the two cohorts completely resolved after subclassifying all cases according to the triple CNA status. The prognostic significance of triple CNA was identified in IDH-wild-type GBM. Distribution difference in prognostic CNA profiles potentially could cause survival differences across cohorts in clinical studies.
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http://dx.doi.org/10.1186/s40478-019-0749-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6580599PMC
June 2019

Author Correction: A missense mutation in the HECT domain of NEDD4L identified in a girl with periventricular nodular heterotopia, polymicrogyria, and cleft palate.

J Hum Genet 2019 Jul;64(7):701-702

Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.

Since the publication of this article, it has been brought to our attention, that the identified mutation (NM_015277: c.2617 G > A; p.Glu873Lys) is identical with the mutation (NM_001144967: c.2677 G > A; p.Glu893Lys) reported by Broix et al (Nature Genetics 48, 1349-1358, 2016 https://doi.org/10.1038/ng.3676 ). Therefore the mutation is not novel but recurrent. Accordingly, the word "novel" should be deleted throughout the article including the title. Thus, the title should read "A missense mutation in the HECT domain of NEDD4L identified in a girl with periventricular nodular heterotopia, polymicrogyria, and cleft palate."
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http://dx.doi.org/10.1038/s10038-019-0610-8DOI Listing
July 2019