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Pair Duplication (pair + duplication)

Distribution by Scientific Domains

Medical Sciences	75%

Selected Abstracts

The melanoma-associated 24 base pair duplication in p16INK4a is functionally impaired

INTERNATIONAL JOURNAL OF CANCER, Issue 4 2005
Therese M. Becker
Abstract Melanoma-associated germline mutations affecting the tumor suppressor and cyclin-dependent kinase (CDK) inhibitor, CDKN2A/p16INK4a, have been identified in over 100 melanoma-prone families worldwide. To predict the melanoma risk for carriers of specific mutations, mutant p16INK4a can be tested in biochemical and cellular assays. In most cases, p16INK4a mutations with predicted disease relation, due to segregation with melanoma, are functionally impaired in such assays. The N-terminal 24 base pair duplication of CDKN2A, however, encodes a p16INK4a variant previously shown to have wild-type function, despite segregating with melanoma in at least 5 melanoma families. To clarify whether the duplication mutation has a cell cycle regulatory defect or behaves like wild-type p16INK4a, we reanalyzed the cell cycle-inhibitory activity of this mutation. Stable cell clones of the p16-null WMM1175 melanoma cell line inducible for ectopic p16INK4a were used in this study. In these cells, p16INK4a expression can be controlled at physiologic levels. Our results show that in comparison to wild-type p16INK4a, the duplication mutant induced weaker S-phase inhibition and cells expressing this mutant form of p16INK4a retained colony formation ability. We also show that the cell cycle-regulatory defect of the p16INK4a duplication mutant was associated with decreased inhibition of pRb phosphorylation even though it retained significant binding to CDK4. © 2005 Wiley-Liss, Inc. [source]

Severe ,0 thalassemia/hemoglobin E disease caused by de novo 22-base pair duplication in the paternal allele of , globin gene

AMERICAN JOURNAL OF HEMATOLOGY, Issue 7 2007
Ponlapat Rojnuckarin
Abstract , Thalassemia is a major public health concern in Southeast Asia. A prevention program has been implemented in Thailand comprising mass carrier screening and genetic testing. In this study, a Thai girl with severe , thalassemia/hemoglobin (Hb) E disease was born from the mother with Hb E trait and the genotypically normal father. DNA sequencing revealed novel 22-bp tandem duplication in the paternal allele of , globin gene, producing a severely truncated product. A short recurring nucleotide at the insertion site suggested a predisposition to this mutation. Therefore, spontaneous , globin mutations occasionally occur in normal population. Its clinical significance is noteworthy in countries with high prevalence of , thalassemia. Am. J. Hematol 2007. © 2006 Wiley-Liss, Inc. [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]