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 neoplasia1,2,3,4. Cytogenetic studies indicate that cells from affected patients show genomic instability often associated with chromosomal rearrangements causing an acquired somatic mosaicism5,6,7,8,9. The gene(s) responsible for RTS remains unknown. The genes responsible for Werner10 and Bloom11 syndromes (WRN and BLM, respectively) have been identified as homologues of Escherichia coli RecQ, which encodes a DNA helicase12 that unwinds double-stranded DNA into single-stranded DNAs. Other eukaryotic homologues thus far identified are human RECQL (Refs 13, 14), Saccharomyces cerevisiae SGS1 (Refs 15,16) and Schizosaccharomyces pombe rqh1+ (ref. 17). We recently cloned two new human helicase genes, RECQL4 at 8q24.3 and RECQL5 at 17q25, which encode members of the RecQ helicase family18. 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.

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Figure 1: Compound heterozygous mutations in RTS patients.
Figure 2: Schematic representation of predicted consequences for truncated RECQ4 helicase molecules generated by mut-1-4.

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Acknowledgements

We thank S. Tahara, G.A. Coetzee and B.E. Henderson for advice and for providing us with the chromosomal DNAs from individuals of Mexican and European ancestries. This work was supported by the Drug Organization (The Organization for Drug ADR Relief, R and D Promotion and Product Review) of the Japanese Government.

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Correspondence to Yasuhiro Furuichi.

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