Nod-like receptor family pyrin domain-containing protein 12 (NLRP12) is one of the critical pattern recognition receptors which participates in the regulation of multiple inflammatory responses. Mutations in

NLRP12

cause exceptionally rare NLRP12-associated autoinflammatory disease (NLRP12-AID). So far

very few patients with NLRP12-AID have been identified worldwide; therefore

data on the clinical phenotype and genetic profile are limited. In this study

we reported 10 patients who presented mainly with periodic fever syndrome or arthritis. Next-generation sequencing (NGS) identified 6 heterozygous mutations of

NLRP12

including 2 novel null mutations. Of the patients

some with same mutations showed different clinical features. Compared to healthy controls

the increased levels of cytokines were revealed in the patients' plasmas

as well as in the supernatants of patients’ cells stimulated with lipopolysaccharide (LPS) or tumor necrosis factor-α (TNF-α). The missense mutations did not change the protein expression; but decreased level of NLRP12 protein was shown in the null mutations. And

in vitro

expression assay demonstrated a truncating protein induced by the frameshift mutation. Further functional studies revealed the deleterious effect of mutations on nuclear factor-kappa B (NF-κB) signaling. Both the null and missense mutations impaired their inhibition of NF-κB activation induced by p65. Collectively

this study reported a relatively large NLRP12-AID case series. Our findings expand the clinical spectrum

and reinforce the diversity of genetic mutations and clinical phenotypes. The NLRP12-associated disorder should be considered when autoinflammatory diseases are encountered in the clinical practice

especially for patients presenting with periodic fever but no other genetic cause identified.