Loss-of-function variant in DNASE1L3 causes a familial form of systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) is a complex autoimmune disease that causes substantial morbidity. As is typical for many other multifactorial disorders, much of the heritability of SLE remains unknown. We identified a rare autosomal recessive form of SLE, in which autozygome analysis revealed a null mutation in the DNASE1L3 gene. The DNASE1L3-related SLE we describe was always pediatric in onset and correlated with a high frequency of lupus nephritis. Our findings confirm the critical role of impaired clearance of degraded DNA in SLE pathogenesis.

Evaluation of all non‐synonymous single nucleotide polymorphisms (SNPs) in the genes encoding human deoxyribonuclease I and I‐like 3 as a functional SNP potentially implicated in autoimmunity

“…Almost all of the non-synonymous SNPs in the genes encoding other members of the human DNase family, DNase I-like 1 [28], I-like 2 [29] and II [30], exhibited a mono-allelic distribution in the same study populations, similarly to those of DNase I and 1L3. Analysis of the genotype distribution of all these SNPs demonstrated that not only the two mutants, p.Val114Met in DNASE1 [31] and p.Trp215GlyfsX2 in DNASE1L3 [12], but also SNPs p.Lys5Ter [9] and p.Val111Met [10] in DNASE1, related to autoimmune diseases reported previously, were not distributed in any of the study populations. With regard to the nonsynonymous SNPs potentially resulting in alterations of in vivo DNase activity, other than p.Arg244Gln in DNASE1, the human DNase family genes showed remarkably low genetic diversity.…”

“…On the other hand, another member of the DNase I family, DNase 1L3, is present in serum in addition to DNase I, and it was assumed that these DNases may be concerned with each other during DNA degradation, providing effective clearance after exposure or release from dying cells [2,16,41]. Furthermore, a lack or reduction of these DNase activities was attributed to mutations identified in the patients [9,10,12,13], and knockout of DNASE1 [14] was associated with the development of SLE. Considering these findings, it is likely that since DNase I and 1L3 are both implicated in the clearance of apoptotic and/or necrotic cell debris, loss and/or functional deficiency of either enzyme could result in failure to clear debris as the origin of nucleosomes, against which an immune response can be induced, resulting in autoimmune dysfunction.…”

“…On the other hand, compared with the activity level of the wild type, the activity levels of Y46H, V70L, D120N, G127R, R143Q, P154A and A168V were significantly high; substitution of Val, 107,133,140,190,192, 231 and 235 might be indispensable. Also, since the C-terminal 13 amino acid residues in the DNase I protein, which partly form an essential part of the active site, were deleted, it is likely that SNP p.Arg244Ter might produce a loss-of-function variant, in the same manner as p.Trp215GlyfsX2 in DNASE1L3 [12].…”

“…Yasutomo et al [9] and Dittmar et al [10] have identified novel nonsense (p.Lys5Ter) and missense (p.Val111Met) mutations that abolished and reduced DNase I activity, respectively, in patients with autoimmune diseases [11]. Recently, in an SLE patient, Al-Mayouf et al [12] found a null mutation resulting from a homozygous 1-bp deletion (c.643delT; p.Trp215GlyfsX2) and also identified homozygosity for a missense mutation (p.Arg206Cys), the latter producing a loss-of-function variant of DNase 1L3 [13]. It has also been reported that DNase I deficient mice develop an SLE-like syndrome [14], and that lupus-prone MRL and NZB/W F1 mice have impaired DNase 1L3 activity [15].…”

The pathogenesis of keratoconus

“…This approach has proven to be powerful for other familial forms of complex disease such as myopia 72 and systemic lupus erythematosus. 73 To date, 17 distinct potential loci for KC are described; 74 however, only three of these loci have been independently replicated, 5q21, 75,76 5q32 75,77 and 14q11. 75,77 Collectively, these findings suggest that there is a high degree of genetic heterogeneity for KC.…”