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Virginia Valentine

Publications and source records attributed to Virginia Valentine.

6 recordsLinked to original sources
PubMed2026

Multiomic approaches identify a rare CCG repeat expansion in BCLAF3 in neurodevelopmental disorders.

BACKGROUND: Tandem repeat expansions have been implicated in various neurological conditions. Here, we present a novel hypermethylated CCG repeat expansion on Xp22 in the 5'UTR of BCLAF3 in males with neurodevelopmental disorders. METHODS: We used patient-derived fibroblasts and neuronal models from a family with BCLAF3 repeat expansions to generate multiomic data and investigate downstream molecular consequences of the repeat expansion. To identify additional affected individuals with BCLAF3 repeat expansions, we screened methylation arrays (n = 12,375) and short-read genomes (n = 15,963) from probands with neurodevelopmental presentations. We also characterized BCLAF3 repeat expansions in the general population using long-read sequencing data (n = 793) and population-level short-read sequencing data (n = 410,076). RESULTS: Long-read sequencing validated hypermethylation of expanded repeats. Patient-derived cells showed repressed BCLAF3 RNA and protein expression. We show that the BCLAF3 CCG repeat expansion constitutes a previously uncharacterized fragile site (FRAXG) that shifts the surrounding chromatin compartment from open euchromatin to closed heterochromatin. Using our multiomic screening approaches, we identified three additional unrelated males and one related male cousin with long-read sequencing validated (n = 2) or short-read sequencing predicted (n = 2) repeat expansions. In one family, the BCLAF3 repeats segregate with more severe phenotypes than expected for the primary diagnoses. Long-read sequencing in three carrier mothers showed skewed X-inactivation against the repeat expansion, highlighting the potential deleterious effect of an allele with an expansion. Expansions were absent in long-read sequencing data from control populations. Assessment of the BCLAF3 repeat expansion in the UK Biobank indicates that it may be ~ 20X rarer than FMR1 repeat expansions. CONCLUSIONS: CCG repeat expansions in the 5'UTR of BCLAF3 likely constitute a novel genetic etiology associated with X-linked neurodevelopmental phenotypes in males. Future work will be essential to delineate the phenotypic spectrum and determine a disease pathomechanism.

BCLAF3↗
PubMed2003

BRAF and FBXW7 (CDC4, FBW7, AGO, SEL10) mutations in distinct subsets of pancreatic cancer: potential therapeutic targets.

The recognition of biologically distinct tumor subsets is fundamental to understanding tumorigenesis. This study investigated the mutational status of the serine/threonine kinase BRAF and the cyclin E regulator FBXW7 (CDC4, FBW7, AGO, SEL10) related to two distinct pancreatic carcinoma subsets: the medullary KRAS2-wild-type and the cyclin E overexpressing tumors, respectively. Among KRAS2-wild-type carcinomas, 33% (3 of 9) contained BRAF V599E mutations; one of which was identified in the pancreatic cancer cell line COLO357. Among 74 KRAS2-mutant carcinomas, no BRAF mutations were identified. Among the KRAS2/BRAF wild-type carcinomas, no mutations within pathway members MEK1, MEK2, ERK1, ERK2, RAP1B, or BAD were found. Using pancreatic cancer microarrays and immunohistochemistry, we determined that 6% (4 of 46 and 5 of 100 in two independent panels) of pancreatic adenocarcinomas overexpress cyclin E. We identified two potential mechanisms for this overexpression including the amplification/gain of CCNE1 gene copies in the Panc-1 and Su86.86 cell lines and a novel somatic homozygous mutation (H460R, in one of 11 pancreatic cancer xenografts having allelic loss) in FBXW7, which was accompanied by cyclin E overexpression by immunohistochemistry. Both BRAF and FBXW7 mutations functionally activate kinase effectors important in pancreatic cancer and extend the potential options for therapeutic targeting of kinases in the treatment of phenotypically distinct pancreatic adenocarcinoma subsets.

Adenocarcinoma↗
PubMed2002

Caspase-9 and Apaf-1 are expressed and functionally active in human neuroblastoma tumor cell lines with 1p36 LOH and amplified MYCN.

Important roles have been suggested for caspase-8, caspase-9 and Apaf-1 in controlling tumor development and their sensitivity to chemotherapeutic agents. Methylation and deletion of Apaf-1 and CASP8 results in the loss of their expression in melanoma and neuroblastoma, respectively, while CASP9 localization to 1p36.1 suggests it is a good candidate tumor suppressor. The status of CASP9 and Apaf-1 expression in numerous neuroblastoma cell lines with/without amplified MYCN and chromosome 1p36 loss-of-heterozygosity (LOH) was therefore examined to test the hypothesis that one or both of these genes are tumor suppressors in neuroblastoma. Although CASP9 is included in the region encompassing 1p36 LOH in all neuroblastoma cell lines examined, the remaining CASP9 allele(s) express a functional caspase-9 enzyme. Apaf-1 is also expressed in all neuroblastoma tumor cell lines examined. Thus, the CASP9 or Apaf-1 genes do not appear to function as tumor suppressors in MYCN amplified neuroblastomas. However, approximately 20% of the neuroblastoma cell lines with methylated CASP8 alleles are also highly resistant to staurosporine (STS)- and radiation-induced cell death, presumably because cytochrome c is not released from mitochondria. This suggests that a second, smaller sub-group of MYCN amplified neuroblastoma tumors exists with defect(s) in apoptotic signaling components upstream of caspase-9 and Apaf-1. Since no consistent differences in Bcl-2, Bcl-x(L) or Bax expression were seen in the STS- and radiation-resistant neuroblastomas, it suggests that a unique mitochondrial signaling factor(s) is responsible for the defect in cytochrome c release in this sub-group of tumors.

Apoptosis↗