CARD15 mutations in familial granulomatosis syndromes: A study of the original Blau syndrome kindred and other families with large‐vessel arteritis and cranial neuropathy

Abstract

Objective. To analyze the CARD15 gene in families with heritable multi-organ granulomatoses, including the original Blau syndrome kindred as well as other families with related granulomatous conditions.Methods. Linkage mapping was performed in 10 families. Observed recombination events were used to exclude regions centromeric or telomeric to 16q12.1, and the Blau gene critical region was refined to <3 cM, corresponding to a physical distance of 3.5 megabasepairs. Based on its known biochemical function, CARD15 was analyzed as a positional candidate for the Blau syndrome susceptibility gene, by direct DNA sequencing.Results. These studies resulted in the identification, in 5 of the families, of 2 sequence variants at position 334 of the gene product (R334W and R334Q). Affected family members from the original Blau syndrome kindred were heterozygous for the R334W missense mutation; mutations at the same position were also observed in several unrelated Blau syndrome families, some of whose phenotypes included large-vessel arteritis and cranial neuropathy. The missense mutations segregated with the disease phenotype in the families, and were not seen in 208 control alleles.Conclusion. These findings demonstrate that CARD15 is an important susceptibility gene for Blau syndrome and for other familial granulomatoses that display phenotypic traits beyond those of classic Blau syndrome.

The Nucleotide-Binding Oligomerization Domain-Like Receptor NLRC5 Is Involved in IFN-Dependent Antiviral Immune Responses

“…Experiments were performed in triplicate. pp , 0.05. of NOD2 are associated with susceptibility for Crohn's disease or Blau syndrome (7)(8)(9)(10)30), whereas NLRP3/NALP3 has been linked to rare hereditary fever syndromes and Crohn's disease (11-14, 31, 32). These genetic findings underscore the importance of NLRs as surveillance proteins for host defense and immunity and point to their potential as novel therapeutic targets (33).…”

A new CARD15 mutation in Blau syndrome

“…13,31 A distinct group of mutations in the same CARD15 gene causes, in heterozygous state, the rare autoinflammatory BS. 9,32 The Mendelian pattern of inheritance indicates that BS mutations are more penetrant and may affect CARD15 function more severely than the common CD-associated variants. Actually, the latter are thought of as recessive, or genedose-dependent, predisposing factors, with an estimated penetrance o4% in homozygotes/compound heterozygotes and even lower in heterozygotes.…”

Role of genetics in pediatric rheumatology

“…The nucleotide oligomerization domain 2 is expressed in myelomonocytic, dendritic, and Paneth cells, and has a significant role in the innate immune system. Most of Blau mutations are constituted by mutations that cause changes of the amino acid arginine in the 334th position (R334W or R334Q) (18,19). In cases when it is clinically difficult to differentiate patients with Blau syndrome from others with inflammatory chronic recurrent arthritis, molecular genetic analysis should be performed for a clear diagnosis.…”