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

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.

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.

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.

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.

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.

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