A Novel NOD2-associated Mutation and Variant Blau Syndrome: Phenotype and Molecular Analysis

ABSTRACT

Purpose: To describe the clinical and molecular implications of a novel mutation in the NOD2/CARD15 gene on a family and its seven affected members.

Methods: We reviewed the clinical presentations of family members who came to our center for refractory uveitis. Genetic testing and molecular testing was performed.

Results: All affected members had adult onset recurrent non-granulomatous panuveitis. The inheritance pattern suggested an autosomal dominant disease and genetic analysis identified a novel mutation in the NOD2 gene that converted amino acid 600 from glutamate to alanine (E600A). Transfection of the E600A NOD2 into human embryonic kidney-293 (HEK293) cells revealed constitutive activation and a reduced ability to respond to the NOD2 ligand, muramyl dipeptide (MDP) as compared with wild-type NOD2.

Conclusions: The E600A mutation in the NOD2 gene may confer a higher penetrance of uveitis but a later onset of milder forms of non-ocular involvement.

Keywords:

• Arthritis
• Blau syndrome
• dermatitis
• early onset sarcoidosis
• NOD2 associated auto-inflammatory disorder
• NOD2/CARD15
• uveitis

DECLARATION OF INTEREST

Dr. C. Stephen Foster declares the following: Consultancies with Aldeyra Therapeutics (Lexington, MA), Bausch & Lomb Surgical, Inc (Rancho Cucamonga, CA), Eyegate Pharma (Waltham, MA), Genentech (South San Francisco, CA), Novartis (Cambridge, MA), pSivida (Watertown, MA). All other authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

Funding is via grants or grants pending with: Aciont (Salt Lake City, UT), Alcon (Aliso Viejo, CA), Aldeyra Therapeutics (Lexington, MA), Bausch & Lomb (Bridgewater, NJ), Clearside Biomedical (Alpharetta, GA), Dompé pharmaceutical (Milan, Italy), Eyegate Pharma (Waltham, MA), Mallinckrodt pharmaceuticals (Dublin, Ireland), Novartis Pharmaceuticals (Cambridge, MA), pSivida (Watertown, MA), Santen (Osaka, Japan). Payment for lectures, including service on speaking bureaus via: Alcon (Aliso Viejo, CA), Allergan (Dublin, Ireland), Mallinckrodt pharmaceuticals (Dublin, Ireland). Stock or stock options from Eyegate Pharma (Waltham, MA).

ACKNOWLEDGMENTS

We acknowledge Dr. Tammy Martin from Oregon Health & Science University, Portland, Oregon for providing the genetic information. We are also thankful to the patients for providing the information.

FUNDING

Husson University School of Pharmacy and Husson University provided funding for the E600A molecular analysis.

Additional information

Funding

Husson University School of Pharmacy and Husson University provided funding for the E600A molecular analysis.