Cellular defects caused by hypomorphic variants of the Bloom syndrome helicase gene BLM

Molecular Genetics & Genomic Medicine
Vivek M Shastri, Kristina H Schmidt

Abstract

Bloom syndrome is an autosomal recessive disorder characterized by extraordinary cancer incidence early in life and an average life expectancy of ~27 years. Premature stop codons in BLM, which encodes a DNA helicase that functions in DNA double-strand-break repair, make up the vast majority of Bloom syndrome mutations, with only 13 single amino acid changes identified in the syndrome. Sequencing projects have identified nearly one hundred single nucleotide variants in BLM that cause amino acid changes of uncertain significance. Here, in addition to identifying five BLM variants incapable of complementing certain defects of Bloom syndrome cells, making them candidates for new Bloom syndrome causing mutations, we characterize a new class of BLM variants that cause some, but not all, cellular defects of Bloom syndrome. We find elevated sister-chromatid exchanges, a delayed DNA damage response and inefficient DNA repair. Conversely, hydroxyurea sensitivity and quadriradial chromosome accumulation, both characteristic of Bloom syndrome cells, are absent. These intermediate variants affect sites in BLM that function in ATP hydrolysis and in contacting double-stranded DNA. Allele frequency and cellular defects suggest candidates for n...Continue Reading

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Citations

Jul 15, 2016·BioMed Research International·Michael A McilhattonJoanna Groden
Feb 23, 2020·Genes·Sonia Vidushi Gupta, Kristina Hildegard Schmidt
Mar 30, 2021·Frontiers in Genetics·Ekjot KaurSagar Sengupta

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Datasets Mentioned

BETA
GM
GM08505
GM00637

Methods Mentioned

BETA
transfection
transfections
chromosomal aberrations
electrophoresis

Software Mentioned

PolyPhen
ImageJ
Polyphen2
OpenComet
Volocity
Exome Variant Server

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