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.

• Authors: Xiaoju Wang, Helena Kuivaniemi, Gina Bonavita, Lysette Mutkus, Ulrike Mau, Edward Blau, Naohiro Inohara, Gabriel Nunez, Gerard Tromp, Charlene J Williams
• Journal: Arthritis and rheumatism (Arthritis Rheum) Vol. 46 Issue 11 Pg. 3041-5 (Nov 2002) ISSN: 0004-3591 [Print] United States
• PMID: 12428248 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Carrier Proteins
• Intracellular Signaling Peptides and Proteins
• NOD2 protein, human
• Nod2 Signaling Adaptor Protein

Topics

• Arteritis (genetics)
• Carrier Proteins (genetics)
• Chromosome Mapping
• Cranial Nerve Diseases (genetics)
• Female
• Genetic Predisposition to Disease (genetics)
• Granulomatous Disease, Chronic (genetics)
• Humans
• Intracellular Signaling Peptides and Proteins
• Male
• Mutation
• Nod2 Signaling Adaptor Protein
• Syndrome