Publications by authors named "Toshifumi Suzuki"

24 Publications

  • Page 1 of 1

Whole exome sequencing of fetal structural anomalies detected by ultrasonography.

J Hum Genet 2020 Nov 3. Epub 2020 Nov 3.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

The objective of this study was to evaluate the efficacy of whole exome sequencing (WES) for the genetic diagnosis of cases presenting with fetal structural anomalies detected by ultrasonography. WES was performed on 19 cases with prenatal structural anomalies. Genomic DNA was extracted from umbilical cords or umbilical blood obtained shortly after birth. WES data were analyzed on prenatal phenotypes alone, and the data were re-analyzed after information regarding the postnatal phenotype was obtained. Based solely on the fetal phenotype, pathogenic, or likely pathogenic, single nucleotide variants were identified in 5 of 19 (26.3%) cases. Moreover, we detected trisomy 21 in two cases by WES-based copy number variation analysis. The overall diagnostic rate was 36.8% (7/19). They were all compatible with respective fetal structural anomalies. By referring to postnatal phenotype information, another candidate variant was identified by a postnatal clinical feature that was not detected in prenatal screening. As detailed phenotyping is desirable for better diagnostic rates in WES analysis, we should be aware that fetal phenotype is a useful, but sometimes limited source of information for comprehensive genetic analysis. It is important to amass more data of genotype-phenotype correlations, especially to appropriately assess the validity of WES in prenatal settings.
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http://dx.doi.org/10.1038/s10038-020-00869-8DOI Listing
November 2020

Efficient detection of copy-number variations using exome data: Batch- and sex-based analyses.

Hum Mutat 2021 Jan 11;42(1):50-65. Epub 2020 Nov 11.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

Many algorithms to detect copy number variations (CNVs) using exome sequencing (ES) data have been reported and evaluated on their sensitivity and specificity, reproducibility, and precision. However, operational optimization of such algorithms for a better performance has not been fully addressed. ES of 1199 samples including 763 patients with different disease profiles was performed. ES data were analyzed to detect CNVs by both the eXome Hidden Markov Model (XHMM) and modified Nord's method. To efficiently detect rare CNVs, we aimed to decrease sequencing biases by analyzing, at the same time, the data of all unrelated samples sequenced in the same flow cell as a batch, and to eliminate sex effects of X-linked CNVs by analyzing female and male sequences separately. We also applied several filtering steps for more efficient CNV selection. The average number of CNVs detected in one sample was <5. This optimization together with targeted CNV analysis by Nord's method identified pathogenic/likely pathogenic CNVs in 34 patients (4.5%, 34/763). In particular, among 142 patients with epilepsy, the current protocol detected clinically relevant CNVs in 19 (13.4%) patients, whereas the previous protocol identified them in only 14 (9.9%) patients. Thus, this batch-based XHMM analysis efficiently selected rare pathogenic CNVs in genetic diseases.
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http://dx.doi.org/10.1002/humu.24129DOI Listing
January 2021

Nonsense variants of result in distinct congenital anomalies.

Hum Genome Var 2020 18;7:26. Epub 2020 Sep 18.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

Herein, we report two female cases with novel nonsense mutations of at Xq25, encoding stromal antigen 2, a component of the cohesion complex. Exome analysis identified c.3097 C>T, p.(Arg1033*) in Case 1 (a fetus with multiple congenital anomalies) and c.2229 G>A, p.(Trp743*) in Case 2 (a 7-year-old girl with white matter hypoplasia and cleft palate). X inactivation was highly skewed in both cases.
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http://dx.doi.org/10.1038/s41439-020-00114-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501222PMC
September 2020

Interferon therapy for pregnant patients with essential thrombocythemia in Japan.

Int J Hematol 2021 Jan 23;113(1):106-111. Epub 2020 Sep 23.

Department of Hematology, Juntendo University School of Medicine, 2-1-1 Hongou, Bunkyoku, Tokyo, 113-8421, Japan.

Essential thrombocythemia (ET) mainly affects the elderly, but can also develop in women of childbearing age. The risk of miscarriage and other complications during pregnancy in ET patients are reported to be higher than that compared to the general population. Therefore, management of pregnancy in ET patients requires special considerations. Several groups recommend interferon (IFN) therapy for ET patients with high-risk pregnancies, but currently no guidelines are available in Japan. We report the outcomes of nine ET patients with ten consecutive high-risk pregnancies. All patients were successfully managed with IFN-α during their pregnancies. All patients also received aspirin and switched to unfractionated heparin around 36 weeks of gestation. As for the seven pregnancies in which IFN-α was started after detection of pregnancy, median platelet counts decreased from 910 to 573 × 10/L after 2 months of IFN-α therapy, and median platelet counts at the time of delivery for all ten pregnancies was 361 × 10/L. All patients gave birth to healthy children. IFN-α was well tolerated, safe, and effective as a cytoreductive therapy for all patients. Although evidence is limited and the use of IFN is not approved in Japan, we suggest considering IFN therapy for high-risk ET pregnancies.
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http://dx.doi.org/10.1007/s12185-020-03001-wDOI Listing
January 2021

Pure 9p duplication syndrome with aplasia of the middle phalanges of the fifth fingers.

Eur J Med Genet 2020 Oct 18;63(10):104005. Epub 2020 Jul 18.

Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine, Tokyo, Japan.

9p duplication syndrome is a common congenital anomaly syndrome with specific facial features, mental and developmental retardations, and characteristic fingers. Pure 9p duplication without other chromosomal structural variations is very rare. It has recently been reported that cases with partial 9p duplication including SMARCA2 have phenotypes overlapping with Coffin-Siris syndrome (CSS). Herein, we present a family with pure 9p duplication syndrome in which phenotypes partially characteristic of CSS were identified. In one of two siblings, X-ray examination revealed hypoplasia of the distal phalanges of the fifth fingers, aplasia of the middle phalanges of the fifth fingers, and aplasia of the distal phalanges of the second to fifth toes. In pure 9p duplication together with our one affected case, 9 out of 14 cases (64.3%), excluding cases whose clinical data were unavailable, presented the absence or hypoplasia of the middle phalanges of fingers or toes. Interestingly, there are no reports on CSS with aplasia or hypoplasia of the middle phalanx. Therefore, this family might suggest that the aplasia or hypoplasia of the middle phalanges of the fifth fingers or toes is a distinct finding that can distinguish between pure 9p duplication and CSS.
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http://dx.doi.org/10.1016/j.ejmg.2020.104005DOI Listing
October 2020

Retraction Note to: Nonsense variants in STAG2 result in distinct sex-dependent phenotypes.

J Hum Genet 2020 09;65(9):811

Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s10038-020-0782-2DOI Listing
September 2020

A recurrent PJA1 variant in trigonocephaly and neurodevelopmental disorders.

Ann Clin Transl Neurol 2020 07 12;7(7):1117-1131. Epub 2020 Jun 12.

Department of Neurodevelopmental Disorder Genetics, Institute of Brain Science, Nagoya City University Graduate School of Medical Science, Nagoya, Aichi, 467-8601, Japan.

Objective: Neurodevelopmental disorders (NDDs) often associate with epilepsy or craniofacial malformations. Recent large-scale DNA analyses identified hundreds of candidate genes for NDDs, but a large portion of the cases still remain unexplained. We aimed to identify novel candidate genes for NDDs.

Methods: We performed exome sequencing of 95 patients with NDDs including 51 with trigonocephaly and subsequent targeted sequencing of additional 463 NDD patients, functional analyses of variant in vitro, and evaluations of autism spectrum disorder (ASD)-like phenotypes and seizure-related phenotypes in vivo.

Results: We identified de novo truncation variants in nine novel genes; CYP1A1, C14orf119, FLI1, CYB5R4, SEL1L2, RAB11FIP2, ZMYND8, ZNF143, and MSX2. MSX2 variants have been described in patients with cranial malformations, and our present patient with the MSX2 de novo truncation variant showed cranial meningocele and partial epilepsy. MSX2 protein is known to be ubiquitinated by an E3 ubiquitin ligase PJA1, and interestingly we found a PJA1 hemizygous p.Arg376Cys variant recurrently in seven Japanese NDD patients; five with trigonocephaly and one with partial epilepsy, and the variant was absent in 886 Japanese control individuals. Pja1 knock-in mice carrying p.Arg365Cys, which is equivalent to p.Arg376Cys in human, showed a significant decrease in PJA1 protein amount, suggesting a loss-of-function effect of the variant. Pja1 knockout mice displayed moderate deficits in isolation-induced ultrasonic vocalizations and increased seizure susceptibility to pentylenetetrazole.

Interpretation: These findings propose novel candidate genes including PJA1 and MSX2 for NDDs associated with craniofacial abnormalities and/or epilepsy.
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http://dx.doi.org/10.1002/acn3.51093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359110PMC
July 2020

Laparoscopic Removal of Modified Vertical Uterine Compression Sutures due to Postoperative Focal Pain.

Surg J (N Y) 2020 Apr 31;6(2):e67-e70. Epub 2020 Mar 31.

Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine, Tokyo, Japan.

Previously we reported laparoscopic removal of compression sutures due to uterine ischemia and related pain, which has two of the difficult aspects: (1) maneuvering the curved needle to perform compression suturing in the narrow surgical field, and (2) distinguishing between the threads of the cesarean section wound sutures versus the vertical compression sutures during removal, as the threads are the same white color. We performed vertical compression sutures for intrapartum hemorrhage with total placental previa, and modified both the needle type and the color of the thread used for uterine compression sutures during cesarean section. After the operation, we performed successful laparoscopic removal of compression sutures for postoperative focal pain. Changing the needle type and color helped to perform operations. The present case supports the concept that the laparoscopic removal of uterine compression suturing is useful for controlling pain in cases where general analgesics are ineffective.
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http://dx.doi.org/10.1055/s-0040-1708865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108947PMC
April 2020

Retrospective study of the recurrence risk of preterm birth in Japan.

J Matern Fetal Neonatal Med 2020 Feb 18:1-5. Epub 2020 Feb 18.

Department of Obstetrics and Gynecology, Juntendo University, Tokyo, Japan.

A history of preterm birth is a risk factor for preterm birth in a future pregnancy, and there are some reports of prevention methods, such as the administration of progesterone. However, the rate of recurrence of preterm birth in Japan has not been clarified, and there is no data for judging whether these preventive methods are effective. To clarify the risk of recurrence of preterm birth and preterm prelabor rupture of membranes (pPROM) in Japan. A retrospective study was conducted using the perinatal registration database of the Japan Obstetrics and Gynecology Society for the Perinatal Center from 2014 to 2016. There were 704,418 subjects, of which 190,990 were excluded those with unknown maternal information, those under the age of 20 years, those with perinatal disease related to preterm birth, and first-time mothers. Logistic model unavailable and multivariate analysis were performed. An analysis of the preterm birth history indicated the risk of preterm birth in the current pregnancy, and the odds ratio for preterm birth recurrence once, twice, and three times or more was 3.3, 6.6, and 7.8, respectively. As a secondary analysis, we analyzed whether the history of pPROM is a risk factor of recurrence of pPROM and found a significant association with an odds ratio of 3.4. Having a preterm birth history increases the risk of recurrence of preterm birth, and the risk of recurrent preterm birth increases as the number of preterm births increases. Although this report is intended for high-risk pregnancies wherein the rate of preterm birth is high, as previously reported, our data indicate that in Japan, preterm birth is a risk factor of recurrent preterm birth.
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http://dx.doi.org/10.1080/14767058.2020.1727435DOI Listing
February 2020

Hereditary angioedema with deep vein thrombosis and pulmonary thromboembolism during pregnancy.

Taiwan J Obstet Gynecol 2019 Nov;58(6):895-896

Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine, Tokyo 113-8421, Japan.

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http://dx.doi.org/10.1016/j.tjog.2019.04.003DOI Listing
November 2019

Fetal umbilical cord cyst may evolve to omphalocele during pregnancy.

J Clin Ultrasound 2020 Mar 14;48(3):181-183. Epub 2019 Nov 14.

Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine, Tokyo, Japan.

Omphalocele is rarely complicated by umbilical cord cysts. In our case, an umbilical cord cyst and fetal ascites were detected at 26 weeks' gestation in a fetus with trisomy 13. This changed to omphalocele with subsequently absorbed fetal ascites at 35 weeks' gestation. We propose two hypotheses. The abdominal wall may have been physically pierced or an omphalocele might have preexisted, and the intestinal tract in the hernia sac was pushed by fetal ascites.
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http://dx.doi.org/10.1002/jcu.22786DOI Listing
March 2020

Genetic abnormalities in a large cohort of Coffin-Siris syndrome patients.

J Hum Genet 2019 Dec 17;64(12):1173-1186. Epub 2019 Sep 17.

Department of Human Genetics, Graduate school of medicine, Yokohama City University, Yokohama, Japan.

Coffin-Siris syndrome (CSS, MIM#135900) is a congenital disorder characterized by coarse facial features, intellectual disability, and hypoplasia of the fifth digit and nails. Pathogenic variants for CSS have been found in genes encoding proteins in the BAF (BRG1-associated factor) chromatin-remodeling complex. To date, more than 150 CSS patients with pathogenic variants in nine BAF-related genes have been reported. We previously reported 71 patients of whom 39 had pathogenic variants. Since then, we have recruited an additional 182 CSS-suspected patients. We performed comprehensive genetic analysis on these 182 patients and on the previously unresolved 32 patients, targeting pathogenic single nucleotide variants, short insertions/deletions and copy number variations (CNVs). We confirmed 78 pathogenic variations in 78 patients. Pathogenic variations in ARID1B, SMARCB1, SMARCA4, ARID1A, SOX11, SMARCE1, and PHF6 were identified in 48, 8, 7, 6, 4, 1, and 1 patients, respectively. In addition, we found three CNVs including SMARCA2. Of particular note, we found a partial deletion of SMARCB1 in one CSS patient and we thoroughly investigated the resulting abnormal transcripts.
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http://dx.doi.org/10.1038/s10038-019-0667-4DOI Listing
December 2019

Comprehensive genetic analysis of 57 families with clinically suspected Cornelia de Lange syndrome.

J Hum Genet 2019 Oct 23;64(10):967-978. Epub 2019 Jul 23.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

Cornelia de Lange syndrome (CdLS) is a rare multisystem disorder with specific dysmorphic features. Pathogenic genetic variants encoding cohesion complex subunits and interacting proteins (e.g., NIPBL, SMC1A, SMC3, HDAC8, and RAD21) are the major causes of CdLS. However, there are many clinically diagnosed cases of CdLS without pathogenic variants in these genes. To identify further genetic causes of CdLS, we performed whole-exome sequencing in 57 CdLS families, systematically evaluating both single nucleotides variants (SNVs) and copy number variations (CNVs). We identified pathogenic genetic changes in 36 out of 57 (63.2 %) families, including 32 SNVs and four CNVs. Two known CdLS genes, NIPBL and SMC1A, were mutated in 23 and two cases, respectively. Among the remaining 32 individuals, four genes (ANKRD11, EP300, KMT2A, and SETD5) each harbored a pathogenic variant in a single individual. These variants are known to be involved in CdLS-like. Furthermore, pathogenic CNVs were detected in NIPBL, MED13L, and EHMT1, along with pathogenic SNVs in ZMYND11, MED13L, and PHIP. These three latter genes were involved in diseases other than CdLS and CdLS-like. Systematic clinical evaluation of all patients using a recently proposed clinical scoring system showed that ZMYND11, MED13L, and PHIP abnormality may cause CdLS or CdLS-like.
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http://dx.doi.org/10.1038/s10038-019-0643-zDOI Listing
October 2019

Nonsense variants in STAG2 result in distinct sex-dependent phenotypes.

J Hum Genet 2019 May 14;64(5):487-492. Epub 2019 Feb 14.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

We herein report two individuals with novel nonsense mutations in STAG2 on Xq25, encoding stromal antigen 2, a component of the cohesion complex. A male fetus (Case 1) clinically presented with holoprosencephaly, cleft palate and lip, blepharophimosis, nasal bone absence, and hypolastic left heart by ultrasonography at 15 gestational weeks. Another female patient (Case 2) showed a distinct phenotype with white matter hypoplasia, cleft palate, developmental delay (DD), and intellectual disability (ID) at 7 years. Whole-exome sequencing identified de novo nonsense mutations in STAG2: c.3097C>T, p.(Arg1033*) in Case 1 and c.2229G>A, p.(Trp743*) in Case 2. X-inactivation was highly skewed in Case 2. To date, only 10 STAG2 pathogenic variants (four nonsense, four missense, and two frameshift) have been reported in patients with multiple congenital anomalies, ID, and DD. Although Case 2 showed similar clinical features to the reported female patients with STAG2 abnormalities, Case 1 showed an extremely severe phenotype, which could be explained by the first detected truncating variant in males.
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http://dx.doi.org/10.1038/s10038-019-0571-yDOI Listing
May 2019

Multiple Placental Infarcts in a Pregnant Woman with Essential Thrombocythemia.

Intern Med 2018 Dec 10;57(24):3647-3650. Epub 2018 Aug 10.

Department of Hematology, Juntendo University School of Medicine, Japan.

Myeloproliferative neoplasms (MPNs), including polycythemia vera, essential thrombocythemia (ET), and primary myelofibrosis, mainly occur in older patients, but have also been reported in younger patients. A "second peak" occurs in female patients in their thirties, particularly in ET; thus, the management of pregnancy is often discussed. We herein present the case of a 33-year-old woman with a high platelet count and multiple placental infarcts during delivery who was subsequently diagnosed with ET. Although there are no worldwide guidelines for the management of MPNs in pregnancy, the risk of thrombosis is markedly increased in these patients, and antithrombotic therapy should be considered.
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http://dx.doi.org/10.2169/internalmedicine.1311-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355404PMC
December 2018

A homozygous NOP14 variant is likely to cause recurrent pregnancy loss.

J Hum Genet 2018 Apr 13;63(4):425-430. Epub 2018 Feb 13.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

Recurrent pregnancy loss is newly defined as more than two consecutive miscarriages. Recurrent pregnancy loss occurs in <5% of total pregnancies. The cause in approximately 40-60% of recurrent pregnancy loss cases remains elusive and must be determined. We investigated two unrelated Iranian consanguineous families with recurrent pregnancy loss. We performed exome sequencing using DNA from a miscarriage tissue and identified a homozygous NOP14 missense variant (c.[136C>G];[136C>G]) in both families. NOP14 is an evolutionally conserved protein among eukaryotes and is required for 18S rRNA processing and 40S ribosome biogenesis. Interestingly, in zebrafish, homozygous mutation of nop14 (possibly loss of function) resulting from retrovirus-mediated insertional mutagenesis led to embryonic lethality at 5 days after fertilization, mimicking early pregnancy loss in humans. Similarly, it is known that the nop14-null yeast is inviable. These data suggest that the homozygous NOP14 mutation is likely to cause recurrent pregnancy loss. Furthermore, this study shows that exome sequencing is very useful to determine the etiology of unsolved recurrent pregnancy loss.
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http://dx.doi.org/10.1038/s10038-018-0410-6DOI Listing
April 2018

Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder.

Cell Rep 2018 01;22(3):734-747

Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan. Electronic address:

Recent studies have established important roles of de novo mutations (DNMs) in autism spectrum disorders (ASDs). Here, we analyze DNMs in 262 ASD probands of Japanese origin and confirm the "de novo paradigm" of ASDs across ethnicities. Based on this consistency, we combine the lists of damaging DNMs in our and published ASD cohorts (total number of trios, 4,244) and perform integrative bioinformatics analyses. Besides replicating the findings of previous studies, our analyses highlight ATP-binding genes and fetal cerebellar/striatal circuits. Analysis of individual genes identified 61 genes enriched for damaging DNMs, including ten genes for which our dataset now contributes to statistical significance. Screening of compounds altering the expression of genes hit by damaging DNMs reveals a global downregulating effect of valproic acid, a known risk factor for ASDs, whereas cardiac glycosides upregulate these genes. Collectively, our integrative approach provides deeper biological and potential medical insights into ASDs.
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http://dx.doi.org/10.1016/j.celrep.2017.12.074DOI Listing
January 2018

Structural development of 1,2,3,4-tetrahydroisoquinoline-type positive allosteric modulators of prostacyclin receptor (IPPAMs) to improve metabolic stability, and investigation of metabolic fate.

Bioorg Med Chem Lett 2017 08 20;27(15):3572-3575. Epub 2017 May 20.

Drug Discovery Initiative, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.

We synthesized a series of 1,2,3,4-tetrahydroisoquinoline-type positive allosteric modulators of prostacyclin receptor (IPPAMs), aiming to improve the metabolic stability of the previously identified hit compound IPPAM-3 (2). Our results indicated that the 3-position of the 2-substituted phenyl ring in this series of IPPAM-3 derivatives is a hot spot for metabolism catalyzed by human hepatic microsomes. This conclusion was confirmed by the finding that 8, in which the 3-position is blocked by a fluorine substituent, exhibited superior metabolic stability (t 21min versus 7min for parent compound 2). The primary route of metabolism of 8 was found to be oxidative defluorination, i.e., ipso-substitution of the fluorine atom to a hydroxyl group, affording catechol derivative 12. The primary metabolite 12 underwent further hydroxylation mainly on the 1,2,3,4-tetrahydroisoquinoline moiety. These findings should be helpful for design of IPPAMs with longer duration of action.
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http://dx.doi.org/10.1016/j.bmcl.2017.05.040DOI Listing
August 2017

TMEM67 mutations found in a case of Joubert syndrome with renal hypodysplasia.

CEN Case Rep 2016 Nov 21;5(2):137-140. Epub 2016 Jan 21.

Department of Pediatrics, Kyorin University School of Medicine, 6-20-2, Shinkawa, Mitaka, Tokyo, 181-8611, Japan.

Joubert syndrome is a rare inherited cerebellar ataxia with the dysgenesis of the cerebellar vermis, called the molar tooth sign. The combination of a large number of causative genes, more than 27, and the various clinical features involving multiple organs has established many genotypic-phenotypic correlations in Joubert syndrome. TMEM67 is one of the genes that are relatively well established as contributing to Joubert syndrome with liver involvement. Here, we report a 2-month-old boy who was initially treated for urinary tract infection, which further led to the diagnosis of Joubert syndrome accompanied by renal hypodysplasia with two different mutations: c.2522A>C and c.1065 + 4Adel in TMEM67.
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http://dx.doi.org/10.1007/s13730-015-0210-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5413751PMC
November 2016

Synthesis of both enantiomers of 1,2,3,4-tetrahydroisoquinoline derivative IPPAM-1 and enantio-dependency of its positive allosteric modulation of prostacyclin receptor.

Bioorg Med Chem Lett 2017 06 29;27(11):2567-2570. Epub 2017 Mar 29.

Lead Exploration Unit, Drug Discovery Initiative, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. Electronic address:

We present a practical synthesis of both enantiomers of 1,2,3,4-tetrahydroisoquinoline derivative IPPAM-1 (1), which is a positive allosteric modulator (PAM) of prostacyclin receptor (IP) and a candidate for treatment of pulmonary arterial hypertension without the side effects caused by IP agonists. Assay of cAMP production by CHO-K1 cells stably expressing human IP clearly demonstrated that the IPPAM activity resides exclusively on the R-form of 1.
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http://dx.doi.org/10.1016/j.bmcl.2017.03.083DOI Listing
June 2017

Neuroimaging findings in Joubert syndrome with C5orf42 gene mutations: A milder form of molar tooth sign and vermian hypoplasia.

J Neurol Sci 2017 May 1;376:7-12. Epub 2017 Mar 1.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

Purpose: Little is known regarding neuroimaging-genotype correlations in Joubert syndrome (JBTS). To elucidate one of these correlations, we investigated the neuroimaging findings of JBTS patients with C5orf42 mutations.

Materials And Methods: Neuroimaging findings in five JBTS patients with C5orf42 mutations were retrospectively assessed with regard to the infratentorial and supratentorial structures on T1-magnetization prepared rapid gradient echo (MPRAGE), T2-weighted images, and color-coded fractional anisotropy (FA) maps; the findings were compared to those in four JBTS patients with mutations in other genes (including three with AHI1 and one with TMEM67 mutations).

Results: In C5orf42-mutant patients, the infratentorial magnetic resonance (MR) images showed normal or minimally thickened and minimally elongated superior cerebellar peduncles (SCP), normal or minimally deepened interpeduncular fossa (IF), and mild vermian hypoplasia (VH). However, in other patients, all had severe abnormalities in the SCP and IF, and moderate to marked VH. Supratentorial abnormalities were found in one individual in other JBTS. In JBTS with all mutations, color-coded FA maps showed the absence of decussation of the SCP (DSCP).

Conclusion: The morphological neuroimaging findings in C5orf42-mutant JBTS were distinctly mild and made diagnosis difficult. However, the absence of DSCP on color-coded FA maps may facilitate the diagnosis of JBTS.
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http://dx.doi.org/10.1016/j.jns.2017.02.065DOI Listing
May 2017

Precise detection of chromosomal translocation or inversion breakpoints by whole-genome sequencing.

J Hum Genet 2014 Dec 9;59(12):649-54. Epub 2014 Oct 9.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

Structural variations (SVs), including translocations, inversions, deletions and duplications, are potentially associated with Mendelian diseases and contiguous gene syndromes. Determination of SV-related breakpoints at the nucleotide level is important to reveal the genetic causes for diseases. Whole-genome sequencing (WGS) by next-generation sequencers is expected to determine structural abnormalities more directly and efficiently than conventional methods. In this study, 14 SVs (9 balanced translocations, 1 inversion and 4 microdeletions) in 9 patients were analyzed by WGS with a shallow (5 × ) to moderate read coverage (20 × ). Among 28 breakpoints (as each SV has two breakpoints), 19 SV breakpoints had been determined previously at the nucleotide level by any other methods and 9 were uncharacterized. BreakDancer and Integrative Genomics Viewer determined 20 breakpoints (16 translocation, 2 inversion and 2 deletion breakpoints), but did not detect 8 breakpoints (2 translocation and 6 deletion breakpoints). These data indicate the efficacy of WGS for the precise determination of translocation and inversion breakpoints.
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http://dx.doi.org/10.1038/jhg.2014.88DOI Listing
December 2014

De novo SOX11 mutations cause Coffin-Siris syndrome.

Nat Commun 2014 Jun 2;5:4011. Epub 2014 Jun 2.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan.

Coffin-Siris syndrome (CSS) is a congenital disorder characterized by growth deficiency, intellectual disability, microcephaly, characteristic facial features and hypoplastic nails of the fifth fingers and/or toes. We previously identified mutations in five genes encoding subunits of the BAF complex, in 55% of CSS patients. Here we perform whole-exome sequencing in additional CSS patients, identifying de novo SOX11 mutations in two patients with a mild CSS phenotype. sox11a/b knockdown in zebrafish causes brain abnormalities, potentially explaining the brain phenotype of CSS. SOX11 is the downstream transcriptional factor of the PAX6-BAF complex, highlighting the importance of the BAF complex and SOX11 transcriptional network in brain development.
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http://dx.doi.org/10.1038/ncomms5011DOI Listing
June 2014

Transcatheter embolization of pulmonary collaterals using liquified gelatin.

Pediatr Int 2003 Aug;45(4):475-7

Departments of Pediatrics and Radiology, Nakadori General Hospital, Akita, Japan.

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http://dx.doi.org/10.1046/j.1442-200x.2003.01759.xDOI Listing
August 2003