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Biomedical subjects

Yoko Aoki

Publications and source records attributed to Yoko Aoki.

27 records · Page 2Linked to original sources
PubMed2004

Mutation analysis of the MMAA and MMAB genes in Japanese patients with vitamin B(12)-responsive methylmalonic acidemia: identification of a prevalent MMAA mutation.

Methylmalonic acidemia (MMA) is caused by the deficient activity of l-methylmalonyl-CoA mutase, which is a vitamin B(12) (or cobalamin, Cbl)-dependent enzyme. MMA due to the effect of insufficient Cbl metabolism is classified into three forms (cblA, cblB, and cblH). Recently, the genes responsible for cblA and cblB were identified as MMAA and MMAB, respectively. The MMAA protein likely transports Cbl into the mitochondria for adenosylcobalamin synthesis, while the MMAB protein appears to be an adenosyltransferase. We performed a mutation analysis of 10 unrelated Japanese patients with vitamin B(12)-responsive MMA. Seven patients had mutations in MMAA, whereas the other three patients showed no disease-causing substitutions in either MMAA or MMAB. Five novel mutations were identified in MMAA (R22X, R145X, L217X, R359G, and 503delC). The 503delC mutation was observed in five of the seven MMAA patients, suggesting that the mutation is prevalent in Japanese patients. This finding may facilitate the DNA diagnosis of vitamin B(12)-responsive MMA within the Japanese population.

Acidosis↗
PubMed2003

Novel IRF6 mutations in Japanese patients with Van der Woude syndrome: two missense mutations (R45Q and P396S) and a 17-kb deletion.

Three Japanese families with Van der Woude syndrome (VWS) were screened for mutations in the interferon regulatory factor 6 gene (IRF6) by sequencing its entire coding region. Two novel missense mutations, R45Q in exon 3 and P396S in exon 9, were identified in families 1 and 2, respectively. In family 3, no causative base change was found by the sequencing analysis, but a deletion involving exons 4-9 was suggested by multiplex PCR analysis. To confirm the deletion and to determine its 5'- and 3'-boundaries, we amplified a DNA fragment containing a heterozygous polymorphic site in exon 2 by using a 5'-upstream forward PCR primer and eight different reverse primers located 3'-downstream of exon 2. The amplified product was subjected to nested PCR to generate a DNA fragment containing the polymorphic site. When a reverse primer located within the deletion was used for the first PCR amplification, only the nondeletion allele was detected after the second PCR. Repeated analyses with eight different reverse primers allowed us to map the boundaries of the deletion, and subsequently a heterozygous 17,162-bp deletion involving exons 4-9 was identified. Since IRF6 mutations in a significant portion of VWS patients remain undetected by conventional sequencing analysis, it may be important to search for a large deletion in those patients. Our simple methods to identify deletions and to determine the boundaries of a deletion would facilitate the identification of such patients.

Cleft Lip↗
PubMed2003

A novel insertion mutation of acetazolamide-responsive episodic ataxia in a Japanese family.

We report a Japanese family with acetazolamide-responsive episodic ataxia. The proband was a 41-year-old woman with interictal nystagmus. She experienced recurrent attacks of loss of equilibrium and loss of coordination of the extremities accompanied by dysarthria and nausea beginning at about 10 years old. These episodes usually lasted for several hours two or three times a week. Direct sequence of CACNA1A demonstrated a novel insertion mutation in the patient and her father. This mutation is estimated to cause early stop of the gene transcription, producing a truncated protein. This is the first report of episodic ataxia type 2 of which the mutation was identified in a Japanese family.

Acetazolamide↗
PubMed2003

Transgenic expression of a dominant-negative connexin26 causes degeneration of the organ of Corti and non-syndromic deafness.

Hereditary deafness affects about 1 in 2000 children and mutations in the GJB2 gene are the major cause in various ethnic groups. GJB2 encodes connexin26, a putative channel component in cochlear gap junction. However, the pathogenesis of hearing loss caused by the GJB2 mutations remains obscure. The generation of a mouse model to study the function of connexin26 during hearing has been hampered by the fact that Gjb2 knockout mice are embryonic lethal. To establish viable model mice we generated transgenic mice expressing a mutant connexin26 with R75W mutation that was identified in a deaf family with autosomal-dominant inheritance. The previous expression analysis revealed that the R75W connexin26 inhibited the gap channel function of the co-expressed normal connexin26 in a dominant-negative fashion. We established two lines of transgenic mice that showed severe to profound hearing loss, deformity of supporting cells, failure in the formation of the tunnel of Corti and degeneration of sensory hair cells. Despite robust expression of the transgene, no obvious structural change was observed in the stria vascularis or spiral ligament that is rich in connexin26 and generates the endolymph. The high resting potential in cochlear endolymph essential for hair cell excitation was normally sustained. These results suggest that the GJB2 mutation disturbs homeostasis of cortilymph, an extracellular space surrounding the sensory hair cells, due to impaired K(+) transport by supporting cells, resulting in degradation of the organ of Corti, rather than affecting endolymph homeostasis in mice and probably in humans.

Amino Acid Substitution↗
PubMed2002

Heterozygous GLDC and GCSH gene mutations in transient neonatal hyperglycinemia.

Transient neonatal hyperglycinemia is clinically or biochemically indistinguishable from nonketotic hyperglycinemia at onset. In the case of transient neonatal hyperglycinemia, the elevated plasma and cerebrospinal fluid glycine levels are normalized within 2 to 8 weeks. To elucidate the pathogenesis of transient neonatal hyperglycinemia, we studied three patients by screening mutations in the genes that encode three components of the glycine cleavage system. Heterozygous mutations were identified in all of the three patients, suggesting that transient neonatal hyperglycinemia develops in some heterozygous carriers for nonketotic hyperglycinemia.

Amino Acid Oxidoreductases↗
PubMed2002

Identification of GFAP gene mutation in hereditary adult-onset Alexander's disease.

Alexander's disease, a leukodystrophy characterized by Rosenthal fibers (RFs) in the brain, is categorized into three subtypes: infantile, juvenile, and adult. Although most are sporadic, occasional familial Alexander's disease cases have been reported for each subtype. Hereditary adult-onset Alexander's disease shows progressive spastic paresis, bulbar or pseudobulbar palsy, palatal myoclonus symptomatologically, and prominent atrophy of the medulla oblongata and upper spinal cord on magnetic resonance imaging. Recent identification of GFAP gene mutations in the sporadic infantile- and juvenile-onset Alexander's disease prompted us to examine the GFAP gene in two Japanese hereditary adult-onset Alexander's disease brothers with autopsy in one case. Both had spastic paresis without palatal myoclonus, and magnetic resonance imaging showed marked atrophy of the medulla oblongata and cervicothoracic cord. The autopsy showed severely involved shrunken pyramids, but scarce Rosenthal fibers (RFs). Moderate numbers of Rosenthal fibers (RFs) were observed in the stratum subcallosum and hippocampal fimbria. In both cases, we found a novel missense mutation of a G-to-T transition at nucleotide 841 in the GFAP gene that results in the substitution of arginine for leucine at amino acid residue 276 (R276L). This is the first report of identification of the causative mutation of the GFAP gene for neuropathologically proven hereditary adult-onset Alexander's disease, suggesting a common molecular mechanism underlies the three Alexander's disease subtypes.

Alexander Disease↗
PubMed2002

Lack of evidence for a significant association between nonsyndromic cleft lip with or without cleft palate and the retinoic acid receptor alpha gene in the Japanese population.

Nonsyndromic cleft lip with or without cleft palate (NSCLP) is one of the most common craniofacial malformations. Both genetic and environmental factors are thought to be involved in the pathogenesis. The retinoic acid receptor alpha ( RARA) is one of the candidate genes for the pathogenesis of NSCLP. An association between a PstI restriction fragment length polymorphism or D17S579 microsatellite marker polymorphism of the RARA gene and NSCLP was previously suggested, but no nucleotide change that may influence the gene expression or the protein sequence has been reported to date. To investigate the possible association between the RARA gene and NSCLP in Japanese patients, we performed a transmission disequilibrium test (TDT) using three microsatellite markers at the RARA locus in 48 parent-offspring trios. The allele-wise TDT did not show evidence of an association between the RARA gene and NSCLP. We also screened nucleotide changes in eight patients with family histories using exon-by-exon direct sequencing. We found a novel nucleotide change (1161C>T) that is located in exon 1 of the RARA gene in one patient whose father also had the disease. Because the 1161C>T was inherited from the patient's healthy mother, the mutation was not considered to be responsible for NSCLP. We then screened all probands for the nucleotide changes in the promoter region of the RARA gene using denaturing high-performance liquid chromatography. A novel nucleotide length polymorphism of a thymidine tract was identified in three patients. No association between this polymorphism and NSCLP was observed. Our findings suggest that the RARA gene variations do not contribute to the development of NSCLP in the Japanese population.

Alleles↗
PubMedDate not supplied

Wild-type phenylalanine hydroxylase activity is enhanced by tetrahydrobiopterin supplementation in vivo: an implication for therapeutic basis of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency.

We previously proposed a novel disease entity, tetrahydrobiopterin (BH4)-responsive phenylalanine hydroxylase (PAH) deficiency, in which administration of BH4 reduced elevated levels of serum phenylalanine [J. Pediatr. 135 (1999) 375-378]. Subsequent reports indicate that the prevalence of BH4-responsive PAH deficiency is much higher than initially anticipated. Although growing attention surrounds treatment with BH4, little is known about the mechanism of BH4 responsiveness. An early report indicates that BH4 concentration in rat liver was 5 microM where Km for BH4 of rat PAH was estimated to be 25 microM in an oxidation experiment using a liver slice, suggesting relative insufficiency of BH4 in liver in vivo. In the present study, we developed a breath test for mice using [1-13C]phenylalanine in order to examine the BH4 responsiveness of normal PAH in vivo. The reliability of the test was verified using BTBR mice and its mutant strain lacking PAH activity, Pahenu2. BH4 supplementation significantly enhanced 13CO2 production in C57BL/6 mice when phenylalanine was pre-loaded. Furthermore, BH4 apparently activated PAH in just 5 min. These observations suggest that submaximal PAH activity occurs at the physiological concentrations of BH4 in vivo, and that PAH activity can be rapidly enhanced by supplementation with BH4. Thus, we propose a possible hypothesis that the responsiveness to BH4 in patients with PAH deficiency is due to the fact that suboptimal physiological concentrations of BH4 are normally present in hepatocytes and the enhancement of the residual activity may be associated with a wide range of mutations.

Animals↗