LACC1

Official Full Name

laccase domain containing 1

Organism

Homo sapiens

GeneID

144811

Background

This gene encodes an oxidoreductase that promotes fatty-acid oxidation, with concomitant inflammasome activation, mitochondrial and NADPH-oxidase-dependent reactive oxygen species production, and bactericidal activity of macrophages. The encoded protein forms a complex with fatty acid synthase on peroxisomes and is thought to be modulated by peroxisome proliferator-activated receptor signaling events. Naturally occurring mutations in this gene are associated with inflammatory bowel disease, Behcet's disease, leprosy, ulcerative colitis, early-onset Crohn's disease, and systemic juvenile idiopathic arthritis. [provided by RefSeq, Apr 2017]

Synonyms

FAMIN; JUVAR; C13orf31;

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Detailed Information

Recent Progress

It has already been indicated by the researchers that human peripheral and intestinal myeloid-derived cells express LACC1. More specifically, LACC1 is expressed in both the cytoplasm and mitochondria. In addition to stimulating the Nod2(a kind of receptor) of human macrophages, LACC1 also associates with the Nod2-signalling complex. Moreover, LACC1 is critical for optimal Nod2-induced signalling, mitochondrial ROS (mtROS) production, cytokine secretion and bacterial clearance.

Recent discovery further proved that variants of LACC1 could play a role in the formation of the recessive form of juvenile arthritis. It appears that age of onset tend to be earlier in patients with LACC1 pathogenic or likely pathogenic variants. Based on the common knowledge on Mendelian inheritance, for the first time, the finding that affected siblings in family E do not share genotypes suggests genetic heterogeneity in familial juvenile arthritis. Further results indicate that pathogenic variants of LACC1 can cause familial juvenile arthritis. Due to the high clinical variability of juvenile arthritis observed, researchers came to propose it can be beneficial for patients and families to screen patients with JIA(Juvenile idiopathic arthritis), especially those with very early onset, for LACC1 variants.

It has been reported that genetic variation at the locus of LACC1 consistently influence the risk of Crohn's disease (CD) and leprosy. Recently, a missense mutation of LACC1 was found both in patients with monogenic forms of CD and systemic juvenile idiopathic arthritis. Thus the researchers proposed that LACC1 single nucleotide polymorphisms (SNPs) are associated with CD and juvenile idiopathic arthritis (JIA, non-systemic), also the ulcerative colitis (UC). UC is another major form of inflammatory bowel disease. To test this hypothesis, investigators selected 11 LACC1 tagged with SNPs, and tested their impact on disease risk in 3855 Swedish individuals from three case-control cohorts of CD, UC and JIA. Findings detected expanded previous results for CD also to UC and JIA.

Considering that the pathological basis of sJIA is still somewhat controversial, especially arguments for both auto-immune and auto-inflammatory etiologies both exist. In order to identify the cause of an autosomal recessive form of sJIA, researchers investigated 13 sJIA patients from 5 consanguineous families, selected from the southern region of Saudi Arabia. Linkage, homozygosity mapping and whole exome sequencing were adopted to identify the disease associated gene and mutation. Linkage analysis revealed that localized sJIA to a region on 13 with a maximal LOD score of 11.33, indicating the strongest linkage to date for this disorder. Homozygosity mapping decreased the critical interval to a 1.02 Mb region, which is defined proximally by rs9533338 and distally by rs9595049. As for whole exome sequencing, a homoallelic missense mutation in LACC1 was identified. It encodes the enzyme (multi-copper oxidoreductase) domain containing 1. Sanger sequencing further confirmed this mutation and segregated with disease in all 5 families. These findings taken together, provide strong genetic evidence that associates mutation of LACC1 with sJIA in the studied families.

A Chinese genome-wide association study (GWAS) depicted novel genes and pathways associated with leprosy susceptibility. Given that it is only partially replicated by independent studies in different ethnicities, researchers described the results of a validation and replication study of the Chinese GWAS in Brazilians, through a stepwise strategy. This study involved two family-based and three independent case-control samples, with 3,614 individuals enrolled. A family-based sample for 36 tag single-nucleotide polymorphisms (SNPs) of five genes was genotyped. These genes are located in four different candidate loci: CCDC122-LACC1, NOD2, TNFSF15 and RIPK2. Association between leprosy and tag SNPs at NOD2 (rs8057431) and CCDC122-LACC1 (rs4942254) was then copied in three additional and independent samples. Findings from these data suggest the NOD2 pathway play a role in the regulation of leprosy susceptibility, across diverse populations. It is suggested by the investigators that LACC1 constitutively associates with succinate dehydrogenase (SDH) subunit A, and promotes pattern recognition receptor (PRR)-induced SDH activity. Relative to LACC1 Ile254, cells transfected with Crohn's disease-risk LACC1 Val254 or LACC1 with mutations of the nearby histidines have decreased PRR-induced outcomes. Relative to LACC1 Ile254 carriers, Val254 disease-risk carrier macrophages indicate reduced PRR-induced mtROS signalling, cytokine secretion and bacterial clearance. These results suggest that LACC1 is critical for promoting PRR-induced outcomes, and this outcome could be attenuated by the LACC1 disease-risk variant.

References:

Karacan, I., et al. "LACC1 Gene Defects in Familial Form of Juvenile Arthritis. " Journal of Rheumatology (2018):726-728.
Assadi, G, et al. "LACC1 polymorphisms in inflammatory bowel disease and juvenile idiopathic arthritis." Genes & Immunity 17.4(2016).
Wakil, Salma M., et al. "Mutation of LACC1 is associated with a Monogenic Form of Systemic Juvenile Idiopathic Arthritis." Arthritis & Rheumatology 67.1(2014):288–295.
Sales-Marques, Carolinne, et al. "NOD2, and CCDC122 - LACC1, genes are associated with leprosy susceptibility in Brazilians." Human Genetics 133.12(2014):1525-1532.
Lahiri, A, et al. "Human LACC1 increases innate receptor-induced responses and a LACC1 disease-risk variant modulates these outcomes. " Nature Communications 8(2017).

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