Human versus chimpanzee chromosome-wide sequence comparison and its evolutionary implication.
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Amino Acid Substitution↗
Biomedical subjects
K J Hsiao
Publications and source records attributed to K J Hsiao.
Detection of Kaposi sarcoma-associated herpesvirus in bone marrow biopsy samples from patients with multiple myeloma.
BACKGROUND: Kaposi sarcoma-associated herpesvirus (KSHV) recently has been identified in the bone marrow (BM) dendritic cell of multiple myeloma (MM) patients. However, whether or not KSHV is associated with MM remains controversial because many studies have failed to detect the presence of KSHV DNA sequences in the BM of their MM patients. METHODS: We have assayed for KSHV DNA sequences in the BM biopsy samples from 49 patients with MM and from 8 patients with normal BM, using nested polymerase chain reaction and dot blot analysis. The polymerase chain reaction product of KSHV was further determined by single-strand conformation polymorphism and sequence analyses. RESULTS: KSHV DNA was detectable in 22 of 49 patients (44.9%) with MM but was not detectable in normal BM cells. Single-strand conformation polymorphism and sequence analyses showed that there were interpatient specific mutations. Sixteen out of 22 KSHV DNA sequences belonged to a previously defined subgroup, and the other 6 remain unclassified and may represent distinct strains of KSHV in Taiwan. CONCLUSIONS: Data strongly supported that KSHV infection did exist in the BM of the current study patients with MM. However, the role of KSHV in the pathogenesis of multiple myeloma remains to be determined.
Adult↗
A genetic factor for age-related cataract: identification and characterization of a novel galactokinase variant, "Osaka," in Asians.
Galactokinase (GALK) deficiency is an autosomal recessive disorder characterized by hypergalactosemia and cataract formation. Through mass screening of newborn infants, we identified a novel and prevalent GALK variant (designated here as the "Osaka" variant) associated with an A198V mutation in three infants with mild GALK deficiency. GALK activity and the amount of immunoreactive protein in the mutant were both 20% of normal construct in expression analysis. The K(m) values for galactose and ATP-Mg(2+) in erythrocytes with homozygous A198V were similar to those of the healthy adult control subjects. A population study for A198V revealed prevalences of 4.1% in Japanese and 2.8% in Koreans, lower incidence in Taiwanese and Chinese, no incidence in blacks and whites from the United States, and a significantly high frequency (7.8%; P < .023) in Japanese individuals with bilateral cataract. This variant probably originated in Japanese and Korean ancestors and is one of the genetic factors that causes cataract in elderly individuals.
Adult↗
Identification of three novel 6-pyruvoyl-tetrahydropterin synthase gene mutations (226C>T, IVS3+1G>A, 116-119delTGTT) in Chinese hyperphenylalaninemia caused by tetrahydrobiopterin synthesis deficiency.
The enzyme 6-Pyruvoyl-tetrahydropterin synthase (PTS) deficiency is the major cause of BH(4)-deficient HPA. The frequency of BH(4)-deficient HPA was estimated to be around 30% among Chinese HPA population in Taiwan, which is much higher than that in Caucasian population (1.5-2% of HPA). Approximately 86% of Chinese BH(4)-deficient HPA was found to be caused by PTS-deficiency. Seven mutations - namely R25G, N52S, V56M, V70D, P87S, D96N, and T106M - had been identified in Chinese PTS-deficient patients previously. In this study, five additional mutations in the PTS gene, namely 200C>T (T67M), 226C>T (L76F), IVS3+1G>A (K54X), 116-119delTGTT (K38X) and 169-171delGTG (V57del), were identified by PCR and DNA sequencing in Chinese PTS-deficient patients. The 116-119delTGTT introduces a frameshift stop after lysine of codon 38 (K38X). The G-to-A transition at the consensus sequence of splicing donor site of exon 3 (IVS3+1G>A) resulted in exon 3 skipping of the PTS transcript and caused a frameshift stop after lysine of codon 54 (K54X). The T67M and V57del mutations have been found in Caucasian PTS deficient patients, while the L76F, IVS3+1G>A, and K38X mutations are novel. None of 100 normal alleles screened was found to have the L76F substitution, which indicated that the L76F substitution is a mutation causing PTS deficiency. Hum Mutat 18:83, 2001.
Alleles↗
A silent mutation induces exon skipping in the phenylalanine hydroxylase gene in phenylketonuria.
An A-->T substitution in cDNA nucleotide 1197 (c.1197A/T) of the human phenylalanine hydroxylase (PAH) gene has been regarded as a silent mutation, because both the wild-type (GUA) and the mutant (GUU) alleles encode a valine residue at codon 399 (V399 V). The nucleotide c.1197 is located at the 3'-end of exon 11at position -3 of the exon-intron junction. To explore whether the substitution exerts any effects on the processing of the PAH mRNA, illegitimate PAH transcripts from lymphoblast cultures of a phenylketonuria (PKU) patient heterozygous for c.1197A/T were analyzed by the polymerase chain reaction following reverse-transcription (RT-PCR). mRNAs with an exon 11 deletion were revealed. Furthermore, by using an R408 W mutation in the paternal allele as a marker, sequence analysis of the RT-PCR products indicates that virtually all PAH transcripts from the maternal allele with the c. 1197A/T substitution do not contain exon 11. To address whether this substitution is the main determinant for exon skipping, PAH minigenes with or without the substitution were constructed and transfected to a human hepatoma cell line. Analysis of the transcription products by S1 nuclease mapping clearly indicated that such exon 11 skipping was directly associated with the c.1197A/T substitution. Thus, this study demonstrates that the c.1197A/T substitution in the PAH gene is not just a neutral polymorphism but a mutation that induces post-transcriptional skipping of exon 11 leading to a PKU phenotype.
Base Sequence↗
Tetrahydrobiopterin-deficient hyperphenylalaninemia in the Chinese.
BACKGROUND: Hyperphenylalaninemia (HPA) may be caused by either a deficiency in phenylalanine-4-hydroxylase or in tetrahydrobiopterin (BH4), the essential cofactor required for the hydroxylation of aromatic amino acids. The most common forms of BH4 deficiency are 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency (MIM 261640) and dihydropteridine reductase (DHPR) deficiency (MIM 261630), which require a different treatment from classical HPA. RESULTS: Approximately 86% of BH4-deficient HPA in the Chinese population was found to be caused by PTPS deficiency. Eleven missense (73C-->G, 120T-->G, 155A-->G, 166G-->A, 200C-->T, 209T-->A, 226C-->T, 259C-->T, 286G-->A, 317C-->T, 430G-->C), one splicing (IVS3+1G-->A) and two deletion mutations (116-119delTGTT, 169-171delGTG) were identified in 37 unrelated PTPS-deficient Chinese families. Among these, 155A-->G, 259C-->T and 286G-->A mutation accounted for about 80% of the mutant alleles. The 155A-->G and 286G-->A mutations were found to be the common mutation in southern and northern Chinese, respectively. Only two Chinese DHPR-deficient families were detected among about 300 Chinese hyperphenylalaninemia cases. A single base transition 508G-->A on the DHPR cDNA was identified in two consanguineous DHPR-deficient siblings. A reduced level of DHPR mRNA expression was found in the other DHPR-deficient patient, which suggested that the mutation might lie in the regulatory region of the DHPR gene. CONCLUSIONS: The BH4-deficient HPA was estimated to make up around 30% of the Chinese population in Taiwan suffering from HPA, which is much higher than in Caucasian populations (1.5-2% of HPA).
5-Hydroxytryptophan↗
Methanol/acetone treatment helps the amplification of FMR1 CGG repeat fragment in dried blood spots from Guthrie cards.
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Acetone↗
Dopa-responsive dystonia induced by a recessive GTP cyclohydrolase I mutation.
GTP cyclohydrolase I (GTPCH) catalyzes the rate-limiting step of tetrahydrobiopterin (BH4) biosynthesis. GTPCH has been associated with two clinically distinct human diseases: the recessive hyperphenylalaninemia (HPA) and the dominant dopa-responsive dystonia (DRD). We found a recessive GTPCH mutation (R249S, 747C-->G in a dystonia patient. Her PHA-stimulated mononuclear blood cells had a normal amount of GTPCH mRNA, but low GTPCH activity. Arginine 249 is located at the C-terminus of GTPCH, outside the catalytic site. E. coli expressed recombinant R249S mutant protein possessed normal enzyme activity and kinetics. However, in transfected eukaryotic cells, R249S mutant protein expression level was lower than the wild-type protein. Therefore, this is suspected to be a destabilizing mutation. Our data suggest that DRD could be either dominantly or recessively inherited, and the inheritance might be determined by the mechanism of mutation.
Amino Acid Substitution↗
Towards metabolic sink therapy for mut methylmalonic acidaemia: correction of methylmalonyl-CoA mutase deficiency in T lymphocytes from a mut methylmalonic acidaemia child by retroviral-mediated gene transfer.
The pathology associated with mut methylmalonic acidaemia (MMA) is caused by systemic accumulation of methylmalonate. Therefore, removal of methylmalonate from the circulation of affected individuals by an engineered metabolic system is proposed as a potential treatment. The haematopoietic cell is a potential site for such a metabolic system because of its direct contact with the accumulated metabolite and the demonstrated safety and ease in utilizing this cell. In this study, we assessed the feasibility of developing a haematopoietic cell-based methylmalonate sink by analysing propionate/methylmalonate metabolism in a variety of haematopoietic cells. The results show that propionate metabolism and methylmalonyl-CoA mutase (MCM) activity are intact in primary T cells, EBV-B cells, and CD34+ haematopoietic stem cell-derived granulocytes, whereas they are defective in those from a mut MMA child. Moreover, normal T and EBV-B cells clear methylmalonate from the medium at a significant rate. Transduction of MCM-deficient T cells with a recombinant retrovirus encoding the human MCM cDNA results in correction of propionate metabolism. These results establish the basis for developing haematopoietic cell-based metabolic sink therapy for mut MMA by T lymphocyte/haematopoietic stem cell-directed gene transfer.
3T3 Cells↗
Towards metabolic sink therapy for mut methylmalonic acidaemia: retrovirus-mediated transfer of the human methylmalonyl-CoA mutase cDNA into peripheral blood progenitor cells of a child with mut methylmalonic acidaemia.
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Antigens, CD34↗
Genetic association study of a polymorphic CAG repeats array of calcium-activated potassium channel (KCNN3) gene and schizophrenia among the Chinese population from Taiwan.
Chandy et al suggested that a novel human neuronal small conductance, calcium-activated potassium channel gene, KCNN3, might be a candidate for schizophrenia. The KCNN3 cDNA sequences contain two stretches of CAG trinucleotide repeats encoding two separate polyglutamine segments near the N-terminus of this channel protein. The second CAG repeat was found to be highly polymorphic in the Caucasian population from both Europe and USA. Upon comparing the allelic frequency distribution between schizophrenic patients and ethnically matched controls, a significant excess of longer CAG repeats in schizophrenic patients was observed. A similar result was obtained in a recent replication study by Bowen et al, performed in Caucasians from UK or Eire. These results suggest an association between the longer CAG repeat allele of the KCNN3 gene and schizophrenia susceptibility. To verify if similar results can be observed in the Chinese population, we carried out a case-control study to compare the allelic frequency distribution of the CAG repeat of the KCNN3 gene between 92 Chinese schizophrenic patients and 100 normal controls from Taiwan. No significant difference of the allelic frequency distribution of the second CAG repeats was detected between the two groups (Wilcoxon Rank Sum test, P = 0.664). In addition, no over-representation of CAG repeats longer than the mode (19 repeats) was found in the patients' group (Fisher's exact test, P = 0.739). Thus, our data do not support that the second polymorphic CAG repeat of the KCNN3 gene may have an association with schizophrenia in our population.
Alleles↗
High seroprevalence of Borna virus infection in schizophrenic patients, family members and mental health workers in Taiwan.
Borna disease virus (BDV), a negative-strand RNA virus, has been reported to be associated with severe psychiatric disorders. The association is mainly based on the findings that patients with schizophrenia and depression have a higher seroprevalence rate of BDV-specific antibodies than controls. In addition, psychiatric patients were also found to have a higher detection rate of BDV transcripts in their blood than controls. By using an improved Western blot analysis, we first demonstrated that Chinese schizophrenic patients from Taiwan also have a higher seroprevalence of BDV-specific antibodies than controls (12.1% vs 2.9%, P< 0.001), providing support to the positive association between BDV and psychiatric disorders in our population. Because of the contagious nature of viral infection, we further examined patients' family members and mental health workers, who have close contact with patients. We found that both groups also have a higher seroprevalence of BDV-specific antibodies, 12.1% and 9.8%, respectively, than controls. This finding provides some evidence for a possible human-to-human transmission of Borna disease virus. Our finding needs further independent verification from other research groups and the clinical relevance of this preliminary observation deserves further study.
Adult↗
Detection of Borna disease virus RNA from peripheral blood cells in schizophrenic patients and mental health workers.
Accumulating evidence suggests that Borna disease virus (BDV), a neurotropic, negative-stranded RNA virus, might be associated with certain human mental disorders. Several research groups reported that psychiatric patients had a significantly higher prevalence of BDV serum antibodies than normal controls. In addition, a significantly higher presence of BDV RNA from peripheral blood cells was identified in mental patients than in controls. In our previous study, we first identified the presence of BDV serum antibodies in a cohort of Chinese schizophrenic patients from Taiwan, and we also demonstrated a significantly higher seroprevalence of BDV antibodies among schizophrenic patients than in non-psychiatric controls. Prompted by the positive seroepidemiological result, we set out to investigate the detection of BDV RNA from the peripheral blood cells of our schizophrenic patients. By using the reverse transcription-polymerase chain reaction (RT-PCR) method, 10 out of 74 Chinese schizophrenic patients from Taiwan were found to have BDV RNA in their blood cells, whereas only one out of 69 controls was positive. The BDV RNA detection rate among schizophrenic patients was significantly higher than that in controls (14% vs 1.4%, P < 0.01). Furthermore, we studied the BDV RNA detection rate among mental health workers, and seven out of 45 mental health workers were found to have positive results. The prevalence rate was significantly higher than that in normal controls (15% vs 1.4%, P < 0.001), which lends further support to our previous finding that mental health workers have a significantly higher presence of BDV serum antibodies. In summary, our data support the finding that BDV infection might be a contributory factor to the pathogenesis of schizophrenia in the Chinese population.
Adult↗
Systematic mutation analysis of the catechol O-methyltransferase gene as a candidate gene for schizophrenia.
OBJECTIVE: Catechol O-methyltransferase (COMT) is involved in the degradation of catecholamine neurotransmitters. Recent linkage studies of schizophrenia and molecular studies of velocardiofacial syndrome suggest that the COMT gene might be a candidate gene for schizophrenia. METHOD: The authors systematically searched for mutations and microdeletion of the COMT gene in 177 Chinese schizophrenic patients from Taiwan; 99 comparison subjects were also studied. RESULTS: Five molecular variants were identified: c.186C > T at exon 3, c.408C > G at exon 4, c.472G > A at exon 4, c.597G > A at exon 5, and c.821-827insC at the 3' untranslated region. However, no differences in the genotype and haplotype frequencies of these molecular variants between the schizophrenic and comparison subjects were detected. Furthermore, no microdeletion was identified among the patients. CONCLUSIONS: These data suggest that the COMT gene does not play a major role in the pathogenesis of schizophrenia, and the genotypic overlap between schizophrenia and velocardiofacial syndrome was rare in this cohort.
Catechol O-Methyltransferase↗
Classical galactosaemia in Chinese: A case report and review of disease incidence.
We report a case of galactose-1-phosphate uridyl transferase (GALT) deficiency in a full-term Chinese neonate, who presented with atypical biochemical features of hyperammonaemia in addition to the classical presenting features of jaundice and lethargy after feeding. Red cell GALT activity was virtually absent in the patient while 50% of normal activity was found in parents and a sibling. Mutation screening excluded both Q188R and N314D as the causative mutation in GALT gene, which suggested a possible genetic segregation among ethnic groups. Data from a Taiwan screening program suggested that the incidence of the disease was approximately 1 in 400 000 in the Chinese population which was a sixth of that in Caucasian populations.
Ammonia↗
Neonatal screening for glucose-6-phosphate dehydrogenase deficiency in Taiwan.
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzymopathic disease in Taiwan. The mass neonatal screening of G6PD deficiency by fluorometric spot test in Taiwan was started with a pilot program in 1984. The nationwide screening was started on July 1, 1987, and a follow-up system comprising of eighteen referral hospitals, including outlying islands, was organized for confirmatory test, medical care and genetic counseling. From July 1987 to December 1997, 2,971,192 heel blood samples collected on filter paper from 1,143 delivery units were screened by four neonatal screening centers. 46,570 cases were confirmed as G6PD deficiency is estimated to be around 2.1% (male 3.1%, female 0.9%) in Taiwan. The coverage rate of neonatal screening was 99% in 1997. To assess the reliability of the confirmatory test, an external quality assurance (QA) program for G6PD assay was developed. Periodically, 3 or 5 lyophilized quality control materials with different activities of G6PD were sent to each referral hospital by speed post delivery in dry ice. From January 1988 to June 1998, 85 QA services were performed. Two hundred and seven (13.5%) abnormal QA results were found, which were attributed to clerk (11.6%), procedural (16.4%), and instrumental errors (47.3%). In aid to confirm G6PD deficiency, a method to detect the G6PD mutation by using the dried blood samples was developed. The frequencies of the mutant alleles in Taiwan were determined to be 46.8% (1376G > T), 16.2% (1388G > A), 7.9% (95A > G), 6.5% (493A > G), 5.6% (392G >T), 4.6% (1024C > T), 0.5% (487G > A) and 0.5% (519C > G), respectively.
Female↗
Mutation analysis of the 6-pyruvoyl-tetrahydropterin synthase gene in Chinese hyperphenylalaninemia caused by tetrahydrobiopterin synthesis deficiency.
Hyperphenylalaninemia (HPA) may be caused by deficiency of phenylalanine hydroxylase or tetrahydrobiopterin (BH4), the essential cofactor for the aromatic amino acid hydroxylases. 6-Pyruvoyl-tetrahydropterin synthase (PTPS) deficiency is a major cause of BH4 deficient HPA. In this study, seven single base mutations at nucleotides 73 (C>G), 155 (A>G), 166 (G>A), 209 (T>A), 259 (C>T), 286 (G>A), and 317 (C>T) on PTPS cDNA were detected in Chinese PTPS-deficient HPA by polymerase chain reaction and solid phase DNA sequencing. These nucleotide alterations result in R25G, N52S, V56M, V70D, P87S, D96N, and T106M amino acid substitutions, respectively. The R25G, V56M, V70D, and T106M were novel mutations found in PTPS gene. By analysis of 38 PTPS mutant alleles from 19 unrelated Chinese PTPS-deficient HPA families, the allele frequency of these mutations in Chinese PTPS-deficient HPA were determined to be approximately 5.3% (R25G), 34.2% (N52S), 7.9% (V56M), 2.6% (V70D), 36.8% (P87S), 7.9% (D96N), and 2.6% (T106M), respectively. Two common mutations, N52S and P87S, were found to account for 71% of the Chinese PTPS mutant alleles. The N52S mutation accounts for 48% of the southern Chinese PTPS mutation, but only one (9%) of the northern Chinese PTPS mutant allele was found to be N52S, which suggested that the N52S mutation might be southern Chinese. Clinically, the V56M mutation was found to associate with the mild form of PTPS deficiency. However, the R25G, N52S, P87S, and D96N were found mainly in the patients with severe clinical symptom. Using polymerase chain reaction-based mutation analysis, a fetus at risk of PTPS deficiency was diagnosed prenatally to be a carrier of N52S mutation.
Alcohol Oxidoreductases↗
Identification of a novel point mutation (S65T) in alpha-galactosidase A gene in Chinese patients with Fabry disease. Mutations in brief no. 169. Online.
Fabry disease is an X-linked inborn error of sphingolipid catabolism resulting from deficient enzyme activity of alpha-galactosidase A. The molecular defects of human alpha-galactosidase A gene causing Fabry disease have been characterized, including gene rearrangement and point mutations, which show the genetic heterogeneity in Fabry disease. To characterize the molecular defects of these patients, each exon of alpha-galactosidase A gene including intron-exon junctions were PCR amplified using biotin-labelled primer and sequenced using magnetic beads solid-phase sequencing. A G to C transversion was identified in the last nucleotide of exon 1 in two unrelated Chinese patients. This mutation obliterates an EcoN1 restriction site. Family studies show close linkage with the affected family members. Screening of 100 alleles (22 males, 39 females) of unrelated normal Chinese can not find this mutation. This mutation not only changes the amino acid from serine to threonine, but also likely cause splicing defects. To our knowledge, this is the first report of mutation in Chinese patients with Fabry disease, and a novel mutation causing Fabry disease not reported in literature previously.
Adult↗