Mutations in RECQL4 cause a subset of cases of Rothmund-Thomson syndrome

Abstract

Rothmund-Thomson syndrome (RTS; also known as poikiloderma congenitale) is a rare, autosomal recessive genetic disorder characterized by abnormalities in skin and skeleton, juvenile cataracts, premature ageing and a predisposition to neoplasia. Cytogenetic studies indicate that cells from affected patients show genomic instability often associated with chromosomal rearrangements causing an acquired somatic mosaicism. The gene(s) responsible for RTS remains unknown. The genes responsible for Werner and Bloom syndromes (WRN and BLM, respectively) have been identified as homologues of Escherichia coli RecQ, which encodes a DNA helicase that unwinds double-stranded DNA into single-stranded DNAs. Other eukaryotic homologues thus far identified are human RECQL, Saccharomyces cerevisiae SGS1 and Schizosaccharomyces pombe rqh1. We recently cloned two new human helicase genes, RECQL4 at 8q24.3 and RECQL5 at 17q25, which encode members of the RecQ helicase family. Here, we report that three RTS patients carried two types of compound heterozygous mutations in RECQL4. The fact that the mutated alleles were inherited from the parents in one affected family and were not found in ethnically matched controls suggests that mutation of RECQL4 at human chromosome 8q24.3 is responsible for at least some cases of RTS.

Oligonucleotide cleavage and rejoining by topoisomerase III from the hyperthermophilic archaeon Sulfolobus solfataricus: temperature dependence and strand annealing‐promoted DNA religation

“…Of particular interest is the possibility that type IA topoisomerases play a role in resolving the intermediates of DNA replication and recombinational repair (e.g. Holliday or double Holliday junctions) through their association with RecQ-like DNA helicases, which have been found in bacteria (RecQ), yeast (Sgs1, Rqh1) and humans (BLM, WRN, RECQL, RECQ4 and RECQ5) (Irino et al, 1986;Gangloff et al, 1994;Puranam and Blackshear, 1994;Carroll et al, 1995;Ellis et al, 1995;Yu et al, 1996;Stewart et al, 1997;Cogoni and Macino, 1999;Kitao et al, 1999). Mutations in human RecQ homologues have been linked to diseases including Bloom, Werner and Rothmund-Thomson syndromes (Ellis et al, 1995;Yu et al, 1996;Kitao et al, 1999).…”

Top3 Processes Recombination Intermediates and Modulates Checkpoint Activity after DNA Damage

“…Of particular interest, defects in three (of the five so far identified) human RecQ helicases cause Bloom's syndrome (BLM), RothmundThomson syndrome (RECQL4), and Werner's syndrome (WRN) (Ellis et al, 1995; Yu et al, 1996;Kitao et al, 1999). Each of these disorders shows genomic instability associated with a predisposition to the development of various cancers.…”

Bloom's syndrome gene suppresses premature ageing caused by Sgs1 deficiency in yeast

“…Werner's syndrome (WS) and Rothmund±Thomson syndrome (RTS) are rare, autosomal recessive disorders characterized by premature ageing and a predisposition to neoplasia (Rothmund 1868;Thomson 1936;Cerimele et al 1982;Vennos et al 1992;Vennos & James 1995;Goto 1997). Recently, the genes, BLM, WRN, and RECQL4, responsible for BS, WS and RTS, respectively, have been found to be homologues of Escherichia coli recQ and Saccharomyces cerevisiae SGS1 genes, which encode DNA helicases (Nakayama et al 1984;Umezu et al 1990;Ellis et al 1995;Watt et al 1996;Yu et al 1996;Kitao et al 1999).…”

“…Among ®ve kinds of human RecQ helicases cloned, the mutations of WRN or RecQL4 have been known as a cause of premature ageing (Goto 1997; Kitao et al 1999), but little is known about ageing functions of BLM helicase, RECQL (Puranam & Blackshear 1994;Seki et al 1994) and RECQL5 (Kitao et al 1998). Here we show that human BLM can compensate premature ageing and increased homologous recombination at the rDNA loci caused by sgs1 mutation.…”