Chromosome instability and nibrin protein variants in NBS heterozygotes.
Caterina Tanzarella,Antonio Antoccia,Emanuela Spadoni,Alessandra di Masi,Vanna Pecile,Eliana Demori,Raymonda Varon,Gian Luigi Marseglia,Luciano Tiepolo,Paola Maraschio +9 more
TL;DR: The frequency of spontaneous chromosome abnormalities in peripheral blood lymphocytes and the X-ray G2 sensitivity in lymphoblastoid cell lines (LCL) have been evaluated in heterozygous subjects from three unrelated Nijmegen Breakage Syndrome (NBS) families.
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Abstract: The frequency of spontaneous chromosome abnormalities in peripheral blood lymphocytes and the X-ray G2 sensitivity in lymphoblastoid cell lines (LCL) have been evaluated in heterozygous subjects from three unrelated Nijmegen Breakage Syndrome (NBS) families, characterised by different mutations in the NBS1 gene. In all the 13 NBS heterozygotes analysed, we found spontaneous chromosome instability consisting in chromosome and chromatid breakages and rearrangements, while radiosensitivity was similar to that of control LCLs in seven out of eight tested NBS heterozygotes. The densitometric analysis of nibrin by immunoblotting indicated only a slight reduction in some of the LCLs from NBS carriers, whereas the immunoprecipitation assay appears a more reliable tool to detect NBS carriers. By means of immunoprecipitation, we investigated two homozygous and four heterozygous subjects. In the cells of the NBS patient 668, with the mutation 900del25, an alternative form of nibrin with a molecular weight of approximately 55 kDa has been detected. This variant protein, together with the normal p95, was also found in the LCL 34 established from a carrier of the same family. Signals of nibrin with a molecular weight lower than 95 kDa, but higher than that observed in LCLs 668 and 34, were detected also in three carriers from the family with mutation 835del4.
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Citations
Natural genetic variation caused by small insertions and deletions in the human genome
Ryan E. Mills,W. Stephen Pittard,Julienne M. Mullaney,Umar Farooq,Todd Creasy,Anup Mahurkar,David M. Kemeza,Daniel S. Strassler,Chris P. Ponting,Caleb Webber,Scott E. Devine +10 more
TL;DR: Almost 2 million small insertions and deletions (INDELs) that range from 1 bp to 10,000 bp in length in the genomes of 79 diverse humans are reported, indicating that small INDEL variation is likely to be a key factor underlying inherited traits and diseases in humans.
•Journal Article
Nijmegen breakage syndrome
TL;DR: Individuals with Nijmegen breakage syndrome have distinctive facial features that include a sloping forehead, a prominent nose, large ears, a small jaw, and outside corners of the eyes that point upward (upslanting palpebral fissures).
189
The missing link between genetic association and regulatory function
TL;DR: In this article , the authors identify 220 gene-trait pairs in which protein-coding variants influence a complex trait or its Mendelian cognate, and find limited evidence that the baseline expression of trait-related genes explains GWAS associations, whether using colocalization methods (8% of genes implicated), transcription-wide association (2% of gene implicated), or a combination of regulatory annotations and distance (4%of genes implicated).
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An inducible null mutant murine model of Nijmegen breakage syndrome proves the essential function of NBS1 in chromosomal stability and cell viability
Ilja Demuth,Pierre Olivier Frappart,Gabriele Hildebrand,Anna Melchers,Stephan Lobitz,Lars Stöckl,Raymonda Varon,Zdenko Herceg,Karl Sperling,Zhang Qi Wang,Martin Digweed +10 more
TL;DR: It is demonstrated, for the first time, that the common human mutation is hypomorphic and that the expression of a truncated protein is sufficient to restore nibrin's vital cellular functions.
78
NBS1 657del5 mutation may contribute only to a limited fraction of breast cancer cases in Russia.
Konstantin G. Buslov,Aglaya G. Iyevleva,Elena V. Chekmariova,Evgeny N. Suspitsin,Alexandr V. Togo,Ekatherina Sh. Kuligina,Anna P. Sokolenko,Matsko De,Turkevich Ea,Yulia R. Lazareva,Oleg L. Chagunava,Elena M. Bit-Sava,Vladimir Semiglazov,Peter Devilee,Cees J. Cornelisse,Kaido P. Hanson,Evgeny N. Imyanitov +16 more
TL;DR: Overall, the data suggest that the NBS1 657del5 allele may contribute only to a limited fraction of breast cancer cases in Russia.
67
References
The hMre11/hRad50 protein complex and Nijmegen breakage syndrome: linkage of double-strand break repair to the cellular DNA damage response.
James P. Carney,James P. Carney,Richard S. Maser,Heidi A. Olivares,Elizabeth M. Davis,Michelle M. Le Beau,John R. Yates,Lara G. Hays,William F. Morgan,William F. Morgan,John H.J. Petrini +10 more
TL;DR: The isolated p95 gene encoding p95, a member of the hMre11/hRad50 double-strand break repair complex, reveals a direct molecular link between DSB repair and cell cycle checkpoint functions in NBS.
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A new chromosomal instability disorder: the Nijmegen breakage syndrome.
Corry M.R. Weemaes,T.W.J. Hustinx,J. M. J. C. Scheres,P. J. J. Van Munster,J. A. J. M. Bakkeren,R. D. F. M. Taalman +5 more
TL;DR: The similarity of the symptoms in the two sibs, the close consanguinity of their parents and the results of the cytogenetic studies in the family favour the hypothesis that the disorder is an inherited one.
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Nijmegen Breakage Syndrome. The International Nijmegen Breakage Syndrome Study Group.
J.A.P. Hiel,C.M.R. Weemaes,L.P.W.J. van den Heuvel,B.G.M. van Engelen,F.J.M. Gabreëls,Dominique Smeets,C.J.A.M. van der Burgt,K.H. Chrzanowska,E. Bernatowska +8 more
TL;DR: Essential features found in NBS were microcephaly, usually without severe retardation, typical facial appearance, immunodeficiency, chromosomal instability, x ray hypersensitivity, and predisposition to malignancy.
An alternative mode of translation permits production of a variant NBS1 protein from the common Nijmegen breakage syndrome allele
TL;DR: It is proposed that the common NBS1 allele encodes a partially functional protein that diminishes the severity of the NBS phenotype.
227
•Journal Article
Nijmegen breakage syndrome
TL;DR: Individuals with Nijmegen breakage syndrome have distinctive facial features that include a sloping forehead, a prominent nose, large ears, a small jaw, and outside corners of the eyes that point upward (upslanting palpebral fissures).
189