Alleles

Publication Title: 
Blood

Heterozygous mutations of the human telomerase RNA template gene (TERC) have been described in patients with acquired aplastic anemia and the autosomal dominant form of dyskeratosis congenita (DKC). Patients with mutations in both TERC alleles have not yet been reported. Here, we report a patient with DKC who inherited 2 distinct TERC sequence variants from her parents; a deletion (216_229del) in one and a point mutation (37A>G) in the other allele of the TERC gene. Her marrow was hypocellular and showed an abnormal clone [46, XX t(7;21)(q34;q22)].

Author(s): 
Ly, Hinh
Schertzer, Mike
Jastaniah, Wasil
Davis, Jeff
Yong, Siu Li
Ouyang, Qin
Blackburn, Elizabeth H.
Parslow, Tristram G.
Lansdorp, Peter M.
Publication Title: 
Cell

The amplification of ribosomal DNA during development of the somatic macronucleus in Tetrahymena thermophila was analyzed by genetic and molecular biological techniques. We have identified an alternate form of the rDNA, structurally distinguishable from the wild-type by an extra cutting site for Bam HI in its nontranscribed spacer. The altered rDNA was inherited in crosses in a simple Mendelian fashion, consistent with the presence of only one rRNA gene copy per haploid genome in the micronucleus.

Author(s): 
Pan, W. C.
Orias, E.
Flacks, M.
Blackburn, E. H.
Publication Title: 
Cancer Research

The telomerase ribonucleoprotein is a promising target for cancer therapy, as it is highly active in many human malignancies. A novel telomerase targeting approach combines short interfering RNA (siRNA) knockdown of endogenous human telomerase RNA (hTer) with expression of a mutant-template hTer (MT-hTer). Such combination MT-hTer/siRNA constructs induce a rapid DNA damage response, telomere uncapping, and inhibition of cell proliferation in a variety of human cancer cell lines.

Author(s): 
Goldkorn, Amir
Blackburn, Elizabeth H.
Publication Title: 
Experimental Cell Research

Expression of the catalytic subunit of human telomerase, hTERT, extends human primary fibroblast life span. Such life span extension has generally been reported to be accompanied by net telomere lengthening, which led to the hypothesis that it is the telomere lengthening that causes the life span extension. Here we show that hTERT+C and hTERT-FlagC, mutant telomerase proteins with either 10 additional residues or a FLAG epitope added to the hTERT C-terminus, confer significant but limited life span extension to IMR90 human primary lung fibroblasts.

Author(s): 
Kim, Moses
Xu, Lifeng
Blackburn, Elizabeth H.
Publication Title: 
PloS One

Apolipoprotein-?4 (APOE-?4) is a major genetic risk factor for cognitive decline, Alzheimer's disease (AD) and early mortality. An accelerated rate of biological aging could contribute to this increased risk. Here, we determined whether APOE-?4 status impacts leukocyte telomere length (TL) and the rate of cellular senescence in healthy mid-life women and, further, whether hormone replacement therapy (HT) modifies this association. Post-menopausal women (N?=?63, Mean age?=?57.7), all HT users for at least one year, were enrolled in a randomized longitudinal study.

Author(s): 
Jacobs, Emily G.
Kroenke, Candyce
Lin, Jue
Epel, Elissa S.
Kenna, Heather A.
Blackburn, Elizabeth H.
Rasgon, Natalie L.
Publication Title: 
Proceedings of the National Academy of Sciences of the United States of America

A mutation that confers resistance to the drug paromomycin is shown to be in the structural gene that codes for the ribosomal RNA in Tetrahymena. This observation was made by exploiting a variant of the ribosomal DNA that distorts amplification of this locus when a new somatic nucleus develops during conjugation. Because the allelic forms of this locus have a restriction endonuclease site polymorphism, it was possible to correlate drug resistance with presence of a specific allele. The genetic results have been confirmed by sequence analysis (presented elsewhere).

Author(s): 
Bruns, P. J.
Katzen, A. L.
Martin, L.
Blackburn, E. H.
Publication Title: 
Journal of Medical Genetics

Data from the US National Huntington's Disease Roster have been analysed in terms of the difference in age of onset (AO) between affected parents and affected offspring, that is, in terms of 'anticipation'. While mean AO in offspring of affected mothers did not differ greatly from AO in their mothers, the distribution of AO in the offspring of affected fathers falls into two groups, the larger group showing an AO only slightly younger than their affected fathers and a small group whose AO was, on average, 24 years younger than their affected fathers.

Author(s): 
Ridley, R. M.
Frith, C. D.
Crow, T. J.
Conneally, P. M.
Publication Title: 
Journal of Neurology, Neurosurgery, and Psychiatry

OBJECTIVES: Cerebellar haemangioblastoma occurs sporadically or as a component tumour of autosomal dominant von Hippel-Lindau disease. Biallelic inactivation of the VHL tumour suppressor gene, which is located on chromosome 3p, has been shown to be involved in the pathogenesis of both tumour entities. Mechanisms of VHL inactivation are intragenic mutations, mitotic recombination events, and hypermethylation of the promoter region.

Author(s): 
Gl‰sker, S.
Bender, B. U.
Apel, T. W.
van Velthoven, V.
Mulligan, L. M.
Zentner, J.
Neumann, H. P.
Publication Title: 
Biological Psychiatry

Genomic imprinting is an epigenetic phenomenon affecting a small number of genes that leads to expression from only one parental allele. Several imprinted genes are important for neurologic development and function and several neurobehavioral disorders are caused by genetic defects involving imprinted genes. For some genes, the imprinting is tissue specific, leading to biallelic expression in some tissues and monoallelic expression in other tissues.

Author(s): 
Weinstein, L. S.
Publication Title: 
Journal of Neurology, Neurosurgery, and Psychiatry

The genetic analysis of common neurological disorders will be a difficult and protracted endeavour. Genetics is only one of many disciplines that will be required but it has already thrown considerable light on the aetiology of several major neurological disorders through the analysis of rare inherited subgroups. The identification of individual susceptibility genes with variants of smaller effect will be more difficult but there is no sharp demarcation between large and small genetic effects, so that many new and important insights will emerge using existing and new technologies.

Author(s): 
Wright, A. F.

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