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Molecular Etiology (molecular + etiology)

Distribution by Scientific Domains

Medical Sciences	40%
Life Sciences	40%

Selected Abstracts

Second lineage of heart forming region provides new understanding of conotruncal heart defects

CONGENITAL ANOMALIES, Issue 1 2010
Yuji Nakajima
ABSTRACT Abnormal heart development causes various congenital heart defects. Recent cardiovascular biology studies have elucidated the morphological mechanisms involved in normal and abnormal heart development. The primitive heart tube originates from the lateral-most part of the heart forming mesoderm and mainly gives rise to the left ventricle. Then, during the cardiac looping, the outflow tract is elongated by the addition of cardiogenic cells from the both pharyngeal and splanchnic mesoderm (corresponding to anterior and secondary heart field, respectively), which originate from the mediocaudal region of the heart forming mesoderm and are later located anteriorly (rostrally) to the dorsal region of the heart tube. Therefore, the heart progenitors that contribute to the outflow tract region are distinct from those that form the left ventricle. The knowledge that there are two different lineages of heart progenitors in the four-chambered heart provides new understanding of the morphological and molecular etiology of conotruncal heart defects. [source]

Molecular Genetic Study on Angelman Syndrome Patients without a Chromosomal Deletion

EPILEPSIA, Issue 2000
Shinji Saitoh
Purpose: Angelman syndrome (AS) is a ncurobehavioral disorder characterized by severe mental retardation, easily cvoked laughter, ataxic gait, and epilepsy. Epilepsy associated with AS is characterized by early childhood onset gencralized seizures with profound EEG abnormalities. Therefore, AS is a good human model for genetic epilepsy syndromes. Approximately 70% of AS cases are caused by maternal deletions of chromosomc 15q I I-qI3; whereas, 30% are not associated with a chromosomal dcletion. Thcse non-deletion AS patients are caused by paternal uniparental disomy (UPD), imprinting mutation (IM), or loss-or-function mutations of the UBE3A gene, cach of which predisposes different recurrence risk. To elucidate molecular etiology of non-dclction AS patients, we investigated 34 AS patients without a chromosomal deletion. Methods: Thirty sporadic AS patients, and 4 familial AS patients (2 families of 2 sibs) were enrolled to the study. The diagnosis of AS was based on Williams' criteria (Williams et al., Am J Med Genet 1995, 56: 237). Genomic DNA was extracted from peripheral blood by a standard procedure. DNA mcthylation tcst at SNRPN locus and genotyping using 7 highly informative PCR-based polymorphisms within 15q I I - q I3 were carried out to identify UPD and IM. When both UPD and IM were ruled out, the patients were classified :LS non-UPD, non-IM. For thcsc non-UPD, non-1M paticnts, UBE3A mutations were screened by PCR-SSCP analysis using 10 sets ofprimcrs covering all coding exons. Results: Among 30 sporadic patients, I UPD and 3 IM patients were identified, and the remaining 26 patients were classified as non-UPD, non-IM. Among 4 familial patients, 2 sibs from I family were detected as IM, whcrcas 2 sibs from another family were classified as non-UPD, non-IM. No UBE3A mutations were identified within 26 sporadic and 2 familial non-UPD, non-IM patients. Conclusion: Threc molecular classes were identified for noindeletion AS patients. Therefore, the underlying genetic mechanism was dcmonstratcd to be complex for AS patients without a chromosomal deletion. Combination of the DNA methylation test and PCR-based polymorphisms was sufficient to detect UPD and IM patients. Because recurrence risk is low for UPD and high lor IM, systematic molecular investigation including the DNA methylation test and PCR-based polymorphisms should bc donc for non-delction AS paticnts for genetic counscling purpose. A majority of non-deletion patients were classified as noii-UPD, non-1M. Although, approximate 30% of non-UPD, nonIM patients arc rcportcd to have UBE3A mutations, no such mutations were identified in our study. An underlying molecular mechanism was not rcvealcd for this group of patients, and therefore, assessment of recurrence risk was difficult. Further investigation is necessary for noii-UPD, non-1M paticnts. [source]

MicroRNA-195 suppresses tumorigenicity and regulates G1/S transition of human hepatocellular carcinoma cells,

HEPATOLOGY, Issue 1 2009
Teng Xu
Growing evidence indicates that deregulation of microRNAs (miRNAs) contributes to tumorigenesis. Down-regulation of miR-195 has been observed in various types of cancers. However, the biological function of miR-195 is still largely unknown. In this study we aimed to elucidate the pathophysiologic role of miR-195. Our results showed that miR-195 expression was significantly reduced in as high as 85.7% of hepatocellular carcinoma (HCC) tissues and in all of the five HCC cell lines examined. Moreover, introduction of miR-195 dramatically suppressed the ability of HCC and colorectal carcinoma cells to form colonies in vitro and to develop tumors in nude mice. Furthermore, ectopic expression of miR-195 blocked G1/S transition, whereas inhibition of miR-195 promoted cell cycle progression. Subsequent investigation characterized multiple G1/S transition-related molecules, including cyclin D1, CDK6, and E2F3, as direct targets of miR-195. Silencing of cyclin D1, CDK6, or E2F3 phenocopied the effect of miR-195, whereas overexpression of these proteins attenuated miR-195-induced G1 arrest. In addition, miR-195 significantly repressed the phosphorylation of Rb as well as the transactivation of downstream target genes of E2F. These results imply that miR-195 may block the G1/S transition by repressing Rb-E2F signaling through targeting multiple molecules, including cyclin D1, CDK6, and E2F3. Conclusion: Our data highlight an important role of miR-195 in cell cycle control and in the molecular etiology of HCC, and implicate the potential application of miR-195 in cancer therapy. (HEPATOLOGY 2009.) [source]

Phosphoproteomics, oncogenic signaling and cancer research

PROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 21 2008
Poh-Kuan Chong
Abstract The past 5,years have seen an explosion of phosphoproteomics methods development. In this review, using epidermal growth-factor signaling as a model, we will discuss how phosphoproteomics, along with bioinformatics and computational modeling, have impacted key aspects of oncogenic signaling such as in the temporal fine mapping of phosphorylation events, and the identification of novel tyrosine kinase substrates and phosphorylation sites. We submit that the next decade will see considerable exploitation of phosphoproteomics in cancer research. Such a phenomenon is already happening as exemplified by its use in promoting the understanding of the molecular etiology of cancer and target-directed therapeutics. [source]

Mutational spectrum of CDKL5 in early-onset encephalopathies: a study of a large collection of French patients and review of the literature

CLINICAL GENETICS, Issue 4 2009
C Nemos
The CDKL5 gene has been implicated in the molecular etiology of early-onset intractable seizures with infantile spasms (IS), severe hypotonia and atypical Rett syndrome (RTT) features. So far, 48 deleterious alleles have been reported in the literature. We screened the CDKL5 gene in a cohort of 177 patients with early-onset seizures, including 30 men and 10 girls with Aicardi syndrome. The screening was negative for all men as well as for women with Aicardi syndrome, excluding the CDKL5 gene as a candidate for this neurodevelopmental disorder. We report 11 additional de novo mutations in CDKL5 in female patients. For the first time, the MLPA approach allowed the identification of a partial deletion encompassing the promoter and the first two exons of CDKL5. The 10-point mutations consist of five missenses (with recurrent amino acid changes at p.Ala40 and p.Arg178), four splicing variants and a 1-base pair duplication. We present a review of all mutated alleles published in the literature. In our study, the overall frequency of mutations in CDKL5 in women with early-onset seizures is around 8.6%, a result comparable with previous reports. Noteworthy, the CDKL5 mutation rate is high (28%) in women with early-onset seizures and IS. [source]