1.Molecular basis of spinocerebellar ataxias subtype caused by nucleotide repeat expansion in noncoding region.
Chinese Journal of Medical Genetics 2008;25(3):293-296
Hereditary spinocerebellar ataxias(SCA) are mainly caused by trinucleotide (CAG/CAA) repeat expansion in open reading frames of corresponding gene. However, SCA8, SCA10 and SCA12 are caused by nucleotide repeat expansion in noncoding region. Recent researches focus on the pathogenesis and hereditary traits, including the instability of nucleotide repeat, the alteration of penetrance, the bias of gender inheritance and the anticipation. The pathogenesis of these three SCA subtypes is different from other subtypes because the repeat expansion in noncoding region has mild influence on translation of polyQ protein. We suggest that the interference on DNA transcription by the abnormal nucleotide expansion, the post-transcriptional toxic effect of abnormal RNA, and the mechanism of bidirectional expression of repeat expansion transcripts play a critical role on SCA8, SCA10 and SCA12 pathogenesis.
Humans
;
Models, Biological
;
Spinocerebellar Ataxias
;
genetics
;
Trinucleotide Repeat Expansion
;
genetics
2.Research progress in roles of microRNA in polyglutamine diseases.
Yu-ting SHI ; Hong JIANG ; Bei-sha TANG
Chinese Journal of Medical Genetics 2010;27(4):406-409
Polyglutamine (Poly Q) diseases are a group of neurodegenerative disorders, caused by the formation of PolyQ mutants due to trinucleotide repeats expansion in coding regions of disease-causing genes, which eventually lead to selective neuronal degeneration and death with unclarified pathogenesis. As a new type of genetic regulatory factor, microRNA (miRNA) plays an important role in modulating gene expression in eukaryote. During the recent years, more attention was paid to roles and related mechanism of miRNA involving in neurodegenerative disease, especially PolyQ diseases. This review is focused on research progress in roles of miRNA in the pathogenesis of PolyQ diseases.
Eukaryota
;
MicroRNAs
;
genetics
;
physiology
;
Nerve Degeneration
;
Neurodegenerative Diseases
;
genetics
;
Peptides
;
genetics
;
Trinucleotide Repeat Expansion
;
genetics
;
Trinucleotide Repeats
;
genetics
3.Clinical Characteristics, Radiological Features and Gene Mutation in 10 Chinese Families with Spinocerebellar Ataxias.
Jian-Wen CHEN ; Li ZHAO ; Feng ZHANG ; Lan LI ; Yu-Hang GU ; Jing-Yuan ZHOU ; Hui ZHANG ; Ming MENG ; Kai-Hua ZHANG ; Wei-Dong LE ; Chun-Bo DONG
Chinese Medical Journal 2015;128(13):1714-1723
BACKGROUNDSpinocerebellar ataxias (SCAs) are a group of neurodegenerative disorders that primarily cause the degeneration in the cerebellum, spinal cord, and brainstem. We study the clinical characteristics, radiological features and gene mutation in Chinese families with SCAs.
METHODSIn this study, we investigated 10 SCAs Chinese families with SCA1, SCA3/Machado-Joseph disease (MJD), SCA7, SCA8. There were 27 people who were genetically diagnosed as SCA, of which 21 people showed clinical symptoms, and 6 people had no clinical phenotype that we called them presymptomatic patients. In addition, 3 people with cerebellar ataxia and cataracts were diagnosed according to the Harding diagnostic criteria but failed to be recognized as SCAs on genetic testing. Clinical characteristic analyses of each type of SCAs and radiological examinations were performed.
RESULTSWe found that SCA3/MJD was the most common subtype in Han population in China, and the ratio of the pontine tegmentum and the posterior fossa area was negatively correlated with the number of cytosine-adenine-guanine (CAG) repeats; the disease duration was positively correlated with the International Cooperative Ataxia Rating Scale score; and the CAG repeats number of abnormal alleles was negatively correlated with the age of onset.
CONCLUSIONSCollectively our study is a systematic research on SCAs in China, which may help for the clinical diagnosis and prenatal screening of this disease, and it may also aid toward better understanding of this disease.
Adult ; DNA Repeat Expansion ; genetics ; Female ; Humans ; Machado-Joseph Disease ; genetics ; pathology ; Male ; Mutation ; genetics ; Spinocerebellar Ataxias ; genetics ; pathology ; Trinucleotide Repeat Expansion ; genetics
4.RNA Mapping of Mutant Myotonic Dystrophy Protein Kinase 3'-Untranslated Region Transcripts.
Genomics & Informatics 2009;7(4):181-186
Myotonic dystrophy type 1 (DM1), which is a dominantly inherited neurodegenerative disorder, results from a CTG trinucleotide repeat expansion in the 3'-untranslated region (3'-UTR) of the myotonic dystrophy protein kinase (DMPK) gene. Retention of mutant DMPK (mDMPK) transcripts in the nuclei of affected cells has been known to be the main cause of pathogenesis of the disease. Thus, reducing the RNA toxicity through elimination of the mutant RNA has been suggested as one therapeutic strategy against DM1. In this study, we suggested RNA replacement with a trans -splicing ribozyme as an alternate genetic therapeutic approach for amelioration of DM1. To this end, we identified the regions of mDMPK 3'-UTR RNA that were accessible to ribozymes by using an RNA mapping strategy based on a trans - splicing ribozyme library. We found that particularly accessible sites were present not only upstream but also downstream of the expanded repeat sequence. Repair or replacement of the mDMPK transcript with the specific ribozyme will be useful for DM1 treatment through reduction of toxic mutant transcripts and simultaneously restore wild-type DMPK or release nucleus-entrapped mDMPK transcripts to the cytoplasm.
Cytoplasm
;
Myotonic Dystrophy
;
Neurodegenerative Diseases
;
Protein Kinases
;
Protein-Serine-Threonine Kinases
;
Retention (Psychology)
;
RNA
;
RNA, Catalytic
;
Trinucleotide Repeat Expansion
5.Advance in research on spinocerebellar ataxia 17.
Chinese Journal of Medical Genetics 2014;31(1):44-47
Hereditary spinocerebellar ataxia type 17 (SCA17) is an autosomal dominantly inherited progressive degenerative disease of the nervous system. Also known as Huntington's disease-like 4(HDL4), SCA17 mainly features ataxia, muscle dystonia and psychiatric symptoms. The gene predisposing to SCA17 has been mapped and cloned, which encodes a TATA-binding protein (TBP). A CAG repeat expansion in the coding region of TBP gene can cause polyglutamine chain extension in the protein. This paper reviews recent progress in the research on SCA17 in regard to its clinical, etiology, pathology and pathogenesis.
Animals
;
Humans
;
Huntington Disease
;
genetics
;
pathology
;
Spinocerebellar Ataxias
;
genetics
;
pathology
;
TATA-Box Binding Protein
;
genetics
;
Trinucleotide Repeat Expansion
6.Distribution of Alleles and Clinical Manifestation in Patients with Progressive Ataxia Caused by Trinucleotide Repeat Expansion.
Seong Gyu LEE ; Chang Seok KI ; Jong Won KIM ; Jang Soo SUH
The Korean Journal of Laboratory Medicine 2003;23(1):60-66
BACKGROUND: Trinucleotide repeat (TNR) expanded disorders represent a novel class of human mutations, which are characterized by abnormal elongation of the triplet repeat sequence in the human genome and is caused by heritable DNA instability. The aim of this study is to determine the relative frequency, distribution of alleles, and the clinical manifestation of TNR expanded disorders in Korean patients with progressive ataxia. METHODS: A total of 76 clinical specimens that were suspicous of hereditary cerebellar ataxia were submitted from January 1999 to August 2001 and tested for TNR expanded disorders by PCR analysis. RESULTS: Spinocerebellar ataxia (SCA) type 1 was the most common hereditary ataxia (5.3%), while SCA2, SCA3, SCA6, SCA7, and dentatorubral and pallidoluysian atrophy (DRPLA) represented 2.6%, 3.9%, 2.6%, 2.6%, and 1.3% of progressive ataxia patients, respectively. This result is different from previous reports concerning Caucasian, Chinese and Koreans. CONCLUSIONS: This study may provide the basis for the study of TNR expanded disorders in Korean patients. To elucidate the prevalence and frequencies of mutation types in Koreans, a large scale study should be performed.
Alleles*
;
Asian Continental Ancestry Group
;
Ataxia*
;
Atrophy
;
Cerebellar Ataxia
;
DNA
;
Genome, Human
;
Humans
;
Polymerase Chain Reaction
;
Prevalence
;
Spinocerebellar Ataxias
;
Spinocerebellar Degenerations
;
Trinucleotide Repeat Expansion*
;
Trinucleotide Repeats
7.CAG Repeat Expansions in the Patients with Mood Disorder.
Sung En SOHN ; Shinn Won LIM ; Soh Young LEE ; Hye Zin HWANG ; Dong Kyu JIN ; Jeung Euy PARK ; Doh Kwan KIM ; Eyoung KIM
Journal of Korean Neuropsychiatric Association 2000;39(2):373-380
OBJECTIVES: The genetic facotrs have been suggested for the etiology of mood disorders but the mode of inheritance is complex. Increased severity and an earlier onset of the bipolar and major depressive disorder over generations within families(Anticipation) were reported. In order to test the hypothesis that trinucleotide repeat expansions underlie the genetic basis of Bipolar and major depressive disorders, we have analyzed the extent of CAG reapeats in genomic DNA from mood disorder patients. METHODS: 55 bipolar disorder, 67 major depressive disorder patients were recruited according to the DSM-III-R criteria. 89 normal controls were recruited from the medical personnel, students and the visitors to the health services center who had no history of psychiatric illness and show normal profile of MMPI. The genomic DNA of patients and controls was analyzed by use of the(CTG) 17 oligonucleotide and the repeat expansion detection(RED) method. The Mann-Whitney U test was used to compare the distribution of the number of CAG repeats among the groups. RESULTS: when the bipolar disorder, major depressive disorder patients were compared with the control group, no significant differences were observed. CONCLUSION: Our results do not support the hypothesis that expanding CAG repeats are causing the observed genetic anticipation in bipolar disorders and major depressive disorders.
Anticipation, Genetic
;
Bipolar Disorder
;
Depressive Disorder, Major
;
DNA
;
Family Characteristics
;
Health Services
;
Humans
;
MMPI
;
Mood Disorders*
;
Trinucleotide Repeat Expansion
;
Trinucleotide Repeats
;
Wills
8.Human FEN-1 can process the 5'-flap DNA of CTG/CAG triplet repeat derived from human genetic diseases by length and sequence dependent manner.
Experimental & Molecular Medicine 2002;34(4):313-317
Trinucleotide repeat (TNR) instability can cause a variety of human genetic diseases including myotonic dystrophy and Huntington's disease. Recent genetic data show that instability of the CAG/CTG repeat DNA is dependent on its length and replication origin. In yeast, the RAD27 (human FEN-1 homologue) null mutant has a high expansion frequency at the TNR loci. We demonstrate here that FEN-1 processes the 5'-flap DNA of CTG/CAG repeats, which is dependent on the length in vitro. FEN-1 protein can cleave the 5'-flap DNA containing triplet repeating sequence up to 21 repeats, but the activity decreases with increasing size of flap above 11 repeats. In addition, FEN-1 processing of 5'-flap DNA depends on sequence, which play a role in the replication origin-dependent TNR instability. Interestingly, FEN-1 can cleave the 5'-flap DNA of CTG repeats better than CAG repeats possibly through the flap-structure. Our biochemical data of FEN-1's activity with triplet repeat DNA clearly shows length dependence, and aids our understanding on the mechanism of TNR instability.
Base Sequence
;
DNA, Single-Stranded/*metabolism
;
Endodeoxyribonucleases/genetics/*metabolism
;
Flap Endonucleases
;
Gene Expression Regulation
;
Genetic Diseases, Inborn/*genetics
;
Human
;
Nucleic Acid Conformation
;
Trinucleotide Repeat Expansion
;
*Trinucleotide Repeats
9.Human FEN-1 can process the 5'-flap DNA of CTG/CAG triplet repeat derived from human genetic diseases by length and sequence dependent manner.
Experimental & Molecular Medicine 2002;34(4):313-317
Trinucleotide repeat (TNR) instability can cause a variety of human genetic diseases including myotonic dystrophy and Huntington's disease. Recent genetic data show that instability of the CAG/CTG repeat DNA is dependent on its length and replication origin. In yeast, the RAD27 (human FEN-1 homologue) null mutant has a high expansion frequency at the TNR loci. We demonstrate here that FEN-1 processes the 5'-flap DNA of CTG/CAG repeats, which is dependent on the length in vitro. FEN-1 protein can cleave the 5'-flap DNA containing triplet repeating sequence up to 21 repeats, but the activity decreases with increasing size of flap above 11 repeats. In addition, FEN-1 processing of 5'-flap DNA depends on sequence, which play a role in the replication origin-dependent TNR instability. Interestingly, FEN-1 can cleave the 5'-flap DNA of CTG repeats better than CAG repeats possibly through the flap-structure. Our biochemical data of FEN-1's activity with triplet repeat DNA clearly shows length dependence, and aids our understanding on the mechanism of TNR instability.
Base Sequence
;
DNA, Single-Stranded/*metabolism
;
Endodeoxyribonucleases/genetics/*metabolism
;
Flap Endonucleases
;
Gene Expression Regulation
;
Genetic Diseases, Inborn/*genetics
;
Human
;
Nucleic Acid Conformation
;
Trinucleotide Repeat Expansion
;
*Trinucleotide Repeats
10.Significance and case analysis of FMR1 mutation screening during early and middle pregnancy.
Qinying CAO ; Weihong MU ; Donglan SUN ; Junzhen ZHU ; Jun GE ; Yuanyuan PENG ; Jing ZHANG
Chinese Journal of Medical Genetics 2021;38(5):450-453
OBJECTIVE:
To screen for mutations of fragile X mental retardation 1 (FMR1) gene during early and middle pregnancy and provide prenatal diagnosis for those carrying high-risk CGG trinucleotide expansions.
METHODS:
Peripheral blood samples of 2316 pregnant women at 12 to 21(+6) gestational weeks were collected for the extraction of genomic DNA. CGG repeats of the FMR1 gene were detected by fluorescence PCR and capillary electrophoresis. Genetic counseling and prenatal diagnosis were provided for 3 women carrying the premutations.
RESULTS:
The carrier rate of CGG repeats of the FMR1 gene was 1 in 178 for the intermediate type and 1 in 772 for the premutation types. The highest frequency allele of CGG was 29 repeats, which accounted for 49.29%, followed by 30 repeats (28.56%) and 36 repeats (8.83%). In case 1, the fetus had a karyotype of 45,X, in addition with premutation type of CGG expansion of the FMR1 gene. Following genetic counseling, the couple chose to terminate the pregnancy through induced labor. The numbers of CGG repeats were respectively 70/- and 29/30 for the husband and wife. In case 2, amniocentesis was performed at 20 weeks of gestation. The number of CGG repeats of the FMR1 gene was 29/-. No abnormality was found in the fetal karyotype and chromosomal copy number variations. The couple chose to continue with the pregnancy. Case 3 refused prenatal diagnosis after genetic counseling and gave birth to a girl at full term, who had a birth weight of 2440 g and no obvious abnormality found during follow-up.
CONCLUSION
Pregnant women should be screened for FMR1 gene mutations during early and middle pregnancy, and those with high-risk CGG expansions should undergo prenatal diagnosis, genetic counseling and family study.
DNA Copy Number Variations
;
Female
;
Fragile X Mental Retardation Protein/genetics*
;
Fragile X Syndrome/genetics*
;
Genetic Counseling
;
Humans
;
Mutation
;
Pregnancy
;
Trinucleotide Repeat Expansion
;
Trinucleotide Repeats