Heterozygous mutations in TREX1 cause familial chilblain lupus and dominant Aicardi-Goutieres syndrome - PubMed (original) (raw)

doi: 10.1086/513443. Epub 2007 Feb 19.

William G Newman, John Dean, Teresa Patrick, Rekha Parmar, Kim Flintoff, Peter Robins, Scott Harvey, Thomas Hollis, Ann O'Hara, Ariane L Herrick, Andrew P Bowden, Fred W Perrino, Tomas Lindahl, Deborah E Barnes, Yanick J Crow

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Heterozygous mutations in TREX1 cause familial chilblain lupus and dominant Aicardi-Goutieres syndrome

Gillian Rice et al. Am J Hum Genet. 2007 Apr.

Abstract

TREX1 constitutes the major 3'-->5' DNA exonuclease activity measured in mammalian cells. Recently, biallelic mutations in TREX1 have been shown to cause Aicardi-Goutieres syndrome at the AGS1 locus. Interestingly, Aicardi-Goutieres syndrome shows overlap with systemic lupus erythematosus at both clinical and pathological levels. Here, we report a heterozygous TREX1 mutation causing familial chilblain lupus. Additionally, we describe a de novo heterozygous mutation, affecting a critical catalytic residue in TREX1, that results in typical Aicardi-Goutieres syndrome.

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Figures

Figure 1.

Figure 1.

Pedigree of the nonconsanguineous family showing vertical transmission of FCL (affected individuals are indicated by blackened symbols). Note that individual II:4 is clinically asymptomatic but carries the familial disease-causing mutation.

Figure 2.

Figure 2.

Skin features observed in FCL-affected family. The lesions are quiescent at present, but there are residual areas of atrophic and hypopigmented skin. Previous ulcerations have led to a loss of ear cartilage and destruction of the PIP joints and distal toes. Note the tapering of the fingers, with tight, shiny skin.

Figure 3.

Figure 3.

TREX1 exonuclease activity. Cell-free protein extracts were assayed for 3′ DNA exonuclease activity with a 3′ labeled poly(dA) substrate after partial purification by column chromatography on single-stranded DNA cellulose. GM0558 is a normal lymphoblastoid control. F39A is a lymphoblastoid cell line from a child with biallelic mutations in TREX1.

Figure 4.

Figure 4.

Skin features seen in the child with AGS due to a de novo heterozygous D200N TREX1 mutation. Ulcerative lesions are seen at the ends of the toes and fingers, and there is a more generalized patchy mottling of the skin, seen here on the legs.

Figure 5.

Figure 5.

Sequence electropherograms illustrating the de novo c.598G→A TREX1 mutation in the child affected with AGS.

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References

Web Resources

    1. GenBank, http://www.ncbi.nlm.nih.gov/GenBank/ (for TREX1 protein [accession numbers AAK07616 and NM_033627, with the A at 2986 as the first base of the initiating ATG codon])
    1. Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim/ (for AGS and FCL) - PubMed

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