Familial Chilblain Lupus, a Monogenic Form of Cutaneous Lupus Erythematosus, Maps to Chromosome 3p

Abstract

Systemic lupus erythematosus is a prototypic autoimmune disease. Apart from rare monogenic deficiencies of complement factors, where lupuslike disease may occur in association with other autoimmune diseases or high susceptibility to bacterial infections, its etiology is multifactorial in nature. Cutaneous findings are a hallmark of the disease and manifest either alone or in association with internal-organ disease. We describe a novel genodermatosis characterized by painful bluish-red inflammatory papular or nodular lesions in acral locations such as fingers, toes, nose, cheeks, and ears. The lesions sometimes appear plaquelike and tend to ulcerate. Manifestation usually begins in early childhood and is precipitated by cold and wet exposure. Apart from arthralgias, there is no evidence for internal-organ disease or an increased susceptibility to infection. Histological findings include a deep inflammatory infiltrate with perivascular distribution and granular deposits of immunoglobulins and complement along the basement membrane. Some affected individuals show antinuclear antibodies or immune complex formation, whereas cryoglobulins or cold agglutinins are absent. Thus, the findings are consistent with chilblain lupus, a rare form of cutaneous lupus erythematosus. Investigation of a large German kindred with 18 affected members suggests a highly penetrant trait with autosomal dominant inheritance. By single-nucleotide-polymorphism-based genomewide linkage analysis, the locus was mapped to chromosome 3p. Haplotype analysis defined the locus to a 13.8-cM interval with a LOD score of 5.04. This is the first description of a monogenic form of cutaneous lupus erythematosus. Identification of the gene responsible for familial chilblain lupus may shed light on the pathogenesis of common forms of connective-tissue disease such as systemic lupus erythematosus.

Dominant Mutations of the TREX1 Exonuclease Gene in Lupus and Aicardi-Goutières Syndrome

“…No Enz, no enzyme. [3][4][5][6][7][8][9][10][11][12][13][14][15] and incubated with the nicked dsDNA plasmid. In these reactions, the catalytically inactive TREX1 D200H-containing enzymes compete with the TREX1 WT to bind the nicked dsDNA plasmid and inhibit degradation by TREX1…”

“…Mutations in the human TREX1 gene have been linked to a spectrum of autoimmune diseases including the severe neurological brain disease Aicardi-Goutières syndrome (AGS) 2 (11), to a monogenic form of cutaneous lupus erythematosus named "familial chilblain lupus" (FCL) (12)(13)(14), to systemic lupus erythematosus (15,16), and to retinal vasculopathy and cerebral leukodystrophy (17). Approximately 40 TREX1 disease-causing missense and frameshift mutations have been identified, mapping to positions located throughout the gene (18,19).…”

The Crystal Structure of TREX1 Explains the 3′ Nucleotide Specificity and Reveals a Polyproline II Helix for Protein Partnering

“…Five distinct mutations within the TREX1 gene were identified as the underlying cause of AGS (22), and a form of systemic lupus erythematosus, familial chilblain lupus, is also known to map to the same genetic locus (23). AGS is a severe neurological brain disease that shares many symptoms with Cree encephalopathy, microcephaly, intracranial calcification syndrome, and systemic lupus erythematosus (42).…”

“…However, Trex1 Ϫ/Ϫ mice show no increase in spontaneous mutation rates but rather display dramatically reduced survival and develop inflammatory myocarditis, indicating a previously unrecognized cellular role for this enzyme (21). Subsequent work has shown that mutations in the human TREX1 gene at the TREX1/AGS1 locus cause Aicardi-Goutières syndrome (22), and a genetic mapping study has further shown that the AGS1 locus overlaps with a locus for chilblain lupus, a form of cutaneous lupus erythematosus (23). These data implicate TREX1 mutations in Aicardi-Goutières syndrome and in systemic lupus erythematosus (22,24,25), consistent with the clinical overlap of these disorders whose pathogenesis is likely related to the accumulation of non-processed DNA replication and repair intermediates and a subsequent aberrant immune response.…”

The TREX1 Double-stranded DNA Degradation Activity Is Defective in Dominant Mutations Associated with Autoimmune Disease

“…The connection between TREX1 and immune activation was first indicated in the Trex1 null mice that develop inflammatory myocarditis consistent with autoimmune disease (11). Mutations in the human TREX1 gene have now been linked to the severe neurological brain disease Aicardi-Goutières syndrome (12), to a monogenic form of cutaneous lupus erythematosus named "familial chilblain lupus" (13)(14)(15), to systemic lupus erythematosus (16), and to retinal vasculopathy and cerebral leukodystrophy (17). The shared TREX1 genetics and similarities in these clinically distinct human disorders point to a common molecular etiology.…”