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. 2002 Jul;71(1):165-7.
doi: 10.1086/341234. Epub 2002 May 9.

Intron-size constraint as a mutational mechanism in Rothmund-Thomson syndrome

Lisa L Wang  1 , Kim Worley, Anu Gannavarapu, Murali M Chintagumpala, Moise L Levy, Sharon E Plon
Affiliations

Intron-size constraint as a mutational mechanism in Rothmund-Thomson syndrome

Lisa L Wang et al. Am J Hum Genet. 2002 Jul.

Abstract

Rothmund-Thomson syndrome (RTS) is an autosomal recessive disorder caused by deleterious mutations in the RECQL4 gene on chromosome 8. The RECQL4 gene structure is unusual because it contains many small introns <100 bp. We describe a proband with RTS who has a novel 11-bp intronic deletion, and we show that this mutation results in a 66-bp intron too small for proper splicing. Constraint on intron size may represent a general mutational mechanism, since human-genome analysis reveals that approximately 15% of genes have introns <100 bp and are therefore susceptible to size constraint. Thus, monitoring of intron size may allow detection of mutations missed by exon-by-exon approaches.

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Figures

Figure 1
Figure 1
Intronic deletion in a proband with RTS. A, Schematic diagram of RECQL4 gene (adapted from Kitao et al. 1999a). The helicase region is unshaded. Asterisks indicate introns <100 bp. B, Sequence of intron 8, showing 11-bp deletion in FCP-102 (boxed), potential branch points (dotted line), and potential intronic splicing enhancer (underline). The sequence used to create the “replaced construct” is shown above the deletion.
Figure 2
Figure 2
RT-PCR showing both splicing error due to intronic deletion and correction of defect by restoration of intron size. A, RT-PCR of lymphoblast RNA from proband FCP-102, his mother, and normal control. Primers are within exons 5 and 11 (between the white arrows in fig. 1A). The normal product is expected to be 791 bp. The aberrant larger product is 857 bp. B, RT-PCR of transcripts from NIH3T3 cells transfected with expression constructs containing exons 5–10 of RECQL4 from wild type, FCP-102, or wild type replaced with 11 unrelated base pairs at the deletion site. Primers are within exons 7 and 9 (between the black arrows in fig. 1A). Predicted sizes are 240 bp, for correct splicing of intron 8; 306 bp, for retention of intron 8 containing the deletion; and 317 bp, for the retention of wild-type intron 8. The highest band in each lane represents retention of introns 7 and 8 (389 bp for FCP-102 and 400 bp for wild type and the replaced construct).
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References

Electronic-Database Information

    1. Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim/ (for RTS [MIM #268400] and RECQL4 [MIM #603780])
    1. UCSC Human Genome Project Working Draft, http://genome.ucsc.edu

References

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