Editors' ChoiceLupus

All in the Family

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Science Translational Medicine  02 Nov 2011:
Vol. 3, Issue 107, pp. 107ec177
DOI: 10.1126/scitranslmed.3003371

The hands-on approach of classical medical training introduces students to different diseases through a series of representative patients. Yet, one might wonder whether the detailed study of individual cases would be that informative, given the complex spectrum of human disease. In the field of genetics, a staggering diversity of susceptibility loci have been identified by using large population-based methods. Is it still possible that detailed genetic investigation of particular cases may provide insight into the disease in a broader sense? A recent study by Al-Mayouf et al. epitomizes this concept; they use a family-based approach and detect a monogenic form of lupus related to a single frame-shift variant in the DNASE1L3 gene, with broad implications for lupus pathogenesis.

Lupus is a severe autoimmune condition that can affect any organ system, most commonly involving the skin, joints, and kidneys. Lupus pathogenesis includes both abnormal activation of the immune system as well as inefficient clearance of dead cellular debris and nucleic acids. In the study by Al-Mayouf et al., the authors identified families in Saudi Arabia with healthy consanguineous parents who had multiple children affected by lupus, which suggests recessive inheritance. In six of the seven families studied, linkage analysis implicated a region on chromosome 3 that contained 206 known genes. In this region, the authors found one single-base frame-shift deletion in the DNASE1L3 gene; this mutation resulted in complete lack of DNASE1L3 activity and could account for the recessive inheritance perfectly in these six families. Lupus affects nine times more women than men, and some common genetic risk factors may play a role in the gender bias. In this monogenic form, it appears that the genetic effect was strong enough to abolish the female predominance of the disease because more than half of the systemic lupus erythematosus cases in these families were male.

The observation that loss of DNASE1L3 activity leads to the complex autoimmune disease lupus in humans suggests that clearance of degraded DNA may be critical for lupus pathogenesis. Indeed, other monogenic forms of lupus that have been reported to date also implicate genes related to clearance of dead cellular debris, emphasizing the importance of this pathway in human lupus. These findings highlight the need of both depth and breadth in scientific research and show that “classic” approaches may be classic for a reason.

S. M. Al-Mayouf et al., Loss-of-function variant in DNASE1L3 causes a familial form of systemic lupus erythematosus. Nat. Genet. 23 October 2011 (10.1038/ng.975). [Abstract]

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