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Shinji Saitoh

Publications and source records attributed to Shinji Saitoh.

At least 19 recordsLinked to original sources
PubMed2026

Biallelic VPS41 Variants in Autosomal Recessive Spinocerebellar Ataxia 29 Resolved by Long-Read Sequencing and RNA Analysis.

BACKGROUND: Biallelic variants in VPS41, encoding a subunit of the HOPS complex, cause autosomal recessive spinocerebellar ataxia 29 (SCAR29), a rare neurodevelopmental disorder with an incompletely defined phenotypic and molecular spectrum. METHODS: We investigated a 24-year-old man with cerebellar ataxia, hypotonia, and intellectual disability. Exome sequencing identified four candidate VPS41 variants. Because maternal DNA was unavailable, long-read genome sequencing was performed to determine allelic configuration, followed by RNA and protein analyses. RESULTS: In addition to typical SCAR29 features, the patient showed previously unreported findings, including swan-neck deformities and pes cavus. Long-read genome sequencing demonstrated that two VPS41 variants were in trans. RNA analysis revealed distinct splicing consequences: one allele produced an out-of-frame transcript predicted to undergo nonsense-mediated decay, whereas the other generated an in-frame exon-skipped transcript. These complementary defects reduced VPS41 expression at both transcript and protein levels, supporting pathogenicity and variant reclassification. CONCLUSION: Our findings expand the phenotypic spectrum of VPS41-related disease and highlight the value of long-read allelic resolution in clarifying pathogenic mechanisms in rare genetic disorders.

Humans↗
PubMed2025

Rescue of imprinted genes by epigenome editing in human cellular models of Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is a genomic imprinting disorder caused by the loss of function of the paternal chromosome 15q11-13, resulting in a spectrum of symptoms associated with hypothalamic dysfunction. PWS patients lack the expression of paternally expressed genes (PEGs) in the 15q11-13 locus but possess an epigenetically silenced set of these genes in the maternal allele. Thus, activation of these silenced genes can serve as a therapeutic target for PWS. Here, we leverage CRISPR-based epigenome editing system to modulate the DNA methylation status of the PWS imprinting control region (PWS-ICR) in induced pluripotent stem cells (iPSCs) derived from PWS patients. Successful demethylation in the PWS-ICR restores the PEG expression from the maternal allele and reorganizes the methylation patterns in other PWS-associated imprinted regions beyond the PWS-ICR. Remarkably, these corrected epigenomic patterns and PEG expression are maintained following the differentiation of these cells into hypothalamic organoids. Finally, the single-cell transcriptomic analysis of epigenome-edited organoids demonstrates a partial restoration of the transcriptomic dysregulation observed in PWS. This study highlights the utility of epigenome editing technology as a therapeutic approach in addressing PWS and potentially other imprinting disorders.

Prader-Willi Syndrome↗
PubMed2006

A new detection method for ATRX gene mutations using a mismatch-specific endonuclease.

X-linked alpha-thalassemia/mental retardation syndrome (ATR-X, OMIM 301040) is a syndromic form of X-linked mental retardation (XLMR). It is caused by a mutation in the ATRX gene, which is also involved in other syndromic forms of XLMR as well as in non-syndromic XLMR, both in males and in females. To analyze the full range of disease-causing mutations for genetic counseling and to establish phenotype-genotype correlations, we have established a new screening method for mutations in the ATRX gene, which uses mismatch-specific endonuclease. We applied this method to confirm 13 known mutations in our patients, some of which have been difficult to be demonstrated by conventional denaturing high-performance liquid chromatography. Furthermore, we found four additional mutations in four ATR-X patients whose clinical diagnosis had not been confirmed at the molecular level. In this method, experimental conditions do not need to be altered depending on mutation sites, and it should be the alternative method for mutation screening.

Base Pair Mismatch↗
PubMed2006

A novel splicing mutation of the ATRX gene in ATR-X syndrome.

X-linked alpha-thalassemia/mental retardation syndrome (ATR-X, MIM#301040) is an X-linked recessive condition affecting males. ATR-X is characterized by severe mental retardation, mild HbH disease, dysmorphic facies, and genital and skeletal abnormalities. ATR-X is caused by mutations in the ATRX gene. Most mutations affect two functionally important domains, the ADD domain and the helicase domain. Here, we report on two brothers with the ATR-X phenotype without HbH disease; both had a mutation in the 5' upstream region of the ADD domain of the ATRX gene. This mutation was a G to T nucleotide substitution at the 3' end of exon 5 and resulted in splicing out of exons 5 and 6. Analysis of cDNA structure may clarify genotype-phenotype correlations in ATR-X because splicing mutation could be detectable only by cDNA analysis.

Adolescent↗
PubMed2005

Non-skewed X-inactivation may cause mental retardation in a female carrier of X-linked alpha-thalassemia/mental retardation syndrome (ATR-X): X-inactivation study of nine female carriers of ATR-X.

X-linked alpha-thalassemia/mental retardation syndrome (ATR-X) is a syndromic form of X-linked mental retardation. We investigated the X-inactivation status of nine female ATR-X carriers by methylation-specific PCR of the HUMARA gene. Six carriers demonstrated a skewed X-inactivation pattern (>90:10) and one showed a non-skewed pattern (72:28), while two were uninformative because of homozygosity for the CAG repeat polymorphic alleles in the HUMARA. Only the carrier mother who showed non-skewed X-inactivation had moderate mental retardation. These findings suggest that mutations in ATRX may cause mental retardation in females, if the X chromosome carrying mutated ATRX is not properly inactivated.

Chromosomes, Human, X↗
PubMed2005

An infantile-juvenile form of Alexander disease caused by a R79H mutation in GFAP.

Alexander disease is a degenerative white matter disorder due to mutations in the glial fibrillary acidic protein (GFAP) gene. It has been classified into three forms based on the age of onset and severity: an infantile, a juvenile, and an adult form. In a 6-year-old patient with a relatively mild form of Alexander disease, we detected a common R79H mutation in GFAP, previously only described in the infantile form. These results suggest the need for further studies of the genotype-phenotype correlation.

Age of Onset↗
PubMed2005

A woman with 46,XX,dup(16)(p13.11 p13.3) and the ATR-X phenotype.

We report a Japanese woman with 46,XX,dup(16)(p13.11p13.3), who closely resembled the phenotype of X-linked alpha-thalassemia/mental retardation syndrome (ATR-X, MIM # 301040). Although she never had alpha-thalassemia, she showed characteristic clinical features including severe mental retardation, characteristic facies and behavior. ATR-X is caused by mutations of the ATRX gene. Although the function of ATRX protein has remained unclarified, it is thought to be involved in the regulation of several genes. The only target gene identified so far is the alpha-globin gene at 16p13.3. Clinical similarity among patients with ATR-X and dup(16)(p13.11p13) may indicate that some target genes regulated by ATRX reside in the duplicated region between 16p13.11 and 16p13.3, and that these genes are abnormally upregulated in ATR-X differently from the alpha-globin gene.

Adult↗
PubMed2005

Uniparental disomy and imprinting defects in Japanese patients with Angelman syndrome.

We examined 54 patients with deletion-negative Angelman syndrome (AS) using DNA methylation testing and microsatellite polymorphism analysis, and identified three patients with paternal uniparental disomy (UPD) and seven patients with imprinting defects (ID). The three patients with UPD were shown to have paternal isodisomy 15, which we hypothesized to have arisen from duplication of chromosome 15. Two of the patients with ID were siblings and carried microdeletions of the imprinting center (IC), while the remaining five patients had no evidence of deletions and represented sporadic cases. Two of the three patients with UPD and two of the seven patients with ID had not developed seizures. The only patients displaying microcephaly were those with ID who had microdeletions at the IC. These data support the previous findings that indicate that patients with UPD and ID may have a milder phenotype of AS.

Angelman Syndrome↗
PubMed2005

Application of magnetoencephalography in epilepsy patients with widespread spike or slow-wave activity.

PURPOSE: To examine whether magnetoencephalography (MEG) can be used to determine patterns of brain activity underlying widespread paroxysms of epilepsy patients, thereby extending the applicability of MEG to a larger population of epilepsy patients. METHODS: We studied two children with symptomatic localization-related epilepsy. Case 1 had widespread spikes in EEG with an operation scar from a resection of a brain tumor; Case 2 had hemispheric slow-wave activity in EEG with sensory auras. MEG was collected with a 204-channel helmet-shaped sensor array. Dynamic statistical parametric maps (dSPMs) were constructed to estimate the cortical distribution of interictal discharges for these patients. Equivalent current dipoles (ECDs) also were calculated for comparison with the results of dSPM. RESULTS: In case 1 with widespread spikes, dSPM presented the major activity at the vicinity of the operation scar in the left frontal lobe at the peak of the spikes, and some activities were detected in the left temporal lobe just before the peak in some spikes. In case 2 with hemispheric slow waves, the most active area was located in the left parietal lobe, and additional activity was seen at the ipsilateral temporal and frontal lobes in dSPM. The source estimates correlated well with the ictal manifestation and interictal single-photon emission computed tomography (SPECT) findings for this patient. In comparison with the results of ECDs, ECDs could not express a prior activity at the left temporal lobe in case 1 and did not model well the MEG data in case 2. CONCLUSIONS: We suggest that by means of dSPM, MEG is useful for presurgical evaluation of patients, not only with localized epileptiform activity, but also with widespread spikes or slow waves, because it requires no selections of channels and no time-point selection.

Adolescent↗
PubMed2005

Dynamic statistical parametric mapping for analyzing the magnetoencephalographic epileptiform activity in patients with epilepsy.

Our current purpose is to evaluate the applicability of dynamic statistical parametric mapping, a novel method for localizing epileptiform activity recorded with magnetoencephalography in patients with epilepsy. We report four pediatric patients with focal epilepsies. Magnetoencephalographic data were collected with a 306-channel whole-head helmet-shaped sensor array. We calculated equivalent current dipoles and dynamic statistical parametric mapping movies of the interictal epileptiform discharges that were based in the minimum-L2 norm estimate, minimizing the square sum of the dipole element amplitudes. The dynamic statistical parametric mapping analysis of interictal epileptiform discharges can demonstrate the rapid change and propagation of interical epileptiform discharges. According to these findings, specific epileptogenic lesion-focal cortical dysplasia could be found and patients could be operated on successfully. The presurgical analysis of interictal epileptiform discharges using dynamic statistical parametric mapping seems to be promising in patients with a possible underlying focal cortical dysplasia and might help to guide the placement of invasive electrodes.

Adolescent↗
PubMed2005

Bilateral germinoma involving the basal ganglia and cerebral white matter.

We describe radiologic findings of germinoma involving bilateral basal ganglia and cerebral white matter. In the early stage, T1-weighted MR images showed hyperintense areas in the bilateral globi pallidi. Later, T2-weighted images showed hyperintense areas involving bilateral white matter. The MR imaging findings reported here could help facilitate the early diagnosis of germ cell tumors in young patients.

Basal Ganglia Diseases↗
PubMed2003

Cerebellar and brainstem involvement in familial juvenile nephronophthisis type I.

We report on an 11-year-old boy with familial juvenile nephronophthisis type I associated with cerebellar ataxia and nystagmus, but not with ocular motor apraxia. An MRI revealed hypoplasia of the brainstem and vermis, and an enlargement of the fourth ventricle. A molecular genetic analysis demonstrated a homozygous deletion including the NPHP1 gene. These findings suggest that NPHP1 may play an important role in the normal development of the brainstem and the cerebellum as well as renal tissue.

Brain Stem↗
PubMed2003

A novel P gene missense mutation in a Japanese patient with oculocutaneous albinism type II (OCA2).

BACKGROUND: Oculocutaneous albinism type II (OCA2) is an autosomal recessively inherited disorder, characterized by white hair and skin, and loss of pigment in the eyes. Mutations in P gene have been shown to result in OCA2. So far, two cases have been reported from Japan. OBJECTIVE: We had an opportunity to examine a case of albinism, and screened the mutations of tyrosinase and P gene. METHODS: Genomic DNA was prepared from peripheral leukocytes. All of the exons and flanking introns of tyrosinase and P gene were PCR-direct-sequenced. RESULTS: Although no mutations were found in tyrosinase, we found two missense substitutions, A481T and Q799H in P gene. The A481T has previously been shown to result in partial function of the P protein. CONCLUSION: The Q799H mutation is not a common polymorphism among normal Japanese, seems most likely to be a pathological OCA2 mutation among Japanese with this form of albinism.

Albinism, Oculocutaneous↗