1996 Fiscal Year Final Research Report Summary
Molecular Analysis and Gene Therapy in Inherited dysmyelinating disorder
| Project/Area Number |
06454308
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pediatrics
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| Research Institution | The Jikei University School of Medicine |
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Principal Investigator |
MAEKAWA Kihei The Jikei University School of Medicine Prof., 小児科, 教授 (80056613)
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| Co-Investigator(Kenkyū-buntansha) |
長谷川 頼康 東京慈恵会医科大学, 小児科, 助手 (60256435)
IDA Hiroyuki The Jikei University School of Medicine assi.prof., 小児科, 講師 (90167255)
OHASHI Touya The Jikei University School of Medicine assi.prof., 小児科, 講師 (60160595)
MATSUSHIMA Hiroshi The Jikei University School of Medicine assi.prof., 小児科, 講師 (70190460)
ETO Yashikatu The Jikei University School of Medicine Prof., 小児科, 教授 (50056909)
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| Project Period (FY) |
1994 – 1996
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| Keywords | MLD / Gaucher Disease / RT-PCR / Arylsulfatase A / PCR-SSCP |
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| Research Abstract |
We investigated the effects of enzyme replacement therapy (ERT) and bone marrow transplantation (BMT) for 15 Japanese patients with Gaucher disease (ERT : 12 cases, BMT : 3 cases). Their phenotypes were classified into possible type 1 (12 cases) and type 3b (3 cases). Laboratory findings (values of hemoglobin, platelet, angiotensin converting enzyme and acid phosphatase) and severity score index (SSI) were improved by treatment in most of cases. However, physical growth, particulary height, was still severely retarded after treatment (pre--2.7SD,post--2.2SD). BMT made physical growth retardation more improved than ERT.Genotype and splenectomy did not influence the responce of treatment. Low dose protocol (60U/kg/dose < 6 months) resulted in bone involvement during treatment in three patients. These data suggest that one should pay attention to physical growth in treatment for pediatric Gaucher disease type 1 patients and the initial dosage of enzyme is the most important factor to obta
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in sufficient clinical effects in ERT.
We have analyzed on the nucleotide sequence of ASA genes in three Japanese patient (case 1,12, and 13) with MLD.In case 1 with late infantile form, two novel mutations were found : a 366a*g transition (designated 366g) in the position -2 of 3' splice site of first intron, and 1542T*C in exon 5 (designated 1542C) causing leucine 298 to be substituted by serine. The analysis of the patient's cDNA fragments amplified by RT-PCR revealed that transcripts of the 366g allele were spliced aberrantly. In a transient expression study, transfectant with the mutant cDNA carrying 298Ser did not show an increase of ASA activity, which confirms the mutation is a cause of late infantile MLD.In case 12 with juvenile form, a pseudodeficiency (PD) allele, which abolishes an N-glycosylation site (350Asn*Ser), was found. This is the first case with PD allele of ASA gene in Japanese origin. However, no disease causing mutation was detected in the case 12. Case 13 with adult form MLD was a compound heterozygote of mutant alleles : 445A of paternal origin and 2330T of maternal origin. The 2330T,affecting splice acceptor site selection, was suggested to be responsible for the mild phenotype in the patient. The further analysis of ASA gene in MLD patients should provide insight into the consideration on the phenotype-genotype correlation in the disorder. Less
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Research Products
(11 results)
