The clinical phenotype and genotype of NLRP12-autoinflammatory disease: a Chinese case series with literature review

Background The nucleotide-binding oligomerization domain-like receptor protein 12(NLRP12)-autoinflammatory disorder(NLRP12-AD)is a rare autoinflammatory disease characterized by recurrent fever,rash as well as musculoskeletal symptoms,which is rarely reported in Asian populations.Methods Three cases of NLRP12-AD presented to our hospital were studied after parental consents were obtained.Clinical presentations were recorded on a standardized case report form.Mutations of NLRP12 were detected by primary immunodeficiency disease panels and further examined by Sanger sequencing.PubMed literature search for relevant studies of systemic autoinflammatory disorders,especially NLRP12-AD between January,2000 and January,2019 was carried and the clinical data were summarized.Comparisons were made between groups in terms of onset age and of ethnicity.Results All our patients presented with fever,rash and arthritis/arthralgia,and sensorineural as well as sensorineural deafness(1/3),uveitis(1/3),abdominal pain(1/3),and myalgia(1/3).Two novel mutation variations,p.W581X and p.L558R,are reported here.In addition,we also found that two patients inherited the mutated alleles from their healthy parents,and this may be evidence of haploinsutficiency.Conclusions Although the genotypes are similar,the clinical manifestations between Chinese patients and Western patients vary thus highlighting the possible influence of ethnic and environmental factors.On the other hand,some genetic mutations may lead to specific phenotype,as we have found a high prevalence of sensorineural hearing loss among p.R284X patients.

Clinical heterogeneity of NLRP12-associated autoinflammatory diseases

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.