Identification of fibronectin 1 as a candidate genetic modifier in a Col4a1 mutant mouse model of Gould syndrome.

Collagen type IV alpha 1 and alpha 2 (COL4A1 and COL4A2) are major components of almost all basement membranes. COL4A1 and COL4A2 mutations cause a multisystem disorder that can affect any organ but typically involves the cerebral vasculature, eyes, kidneys and skeletal muscles. In recent years, patient advocacy and family support groups have united under the name of Gould syndrome. The manifestations of Gould syndrome are highly variable, and animal studies suggest that allelic heterogeneity and genetic context contribute to the clinical variability. We previously characterized a mouse model of Gould syndrome caused by a Col4a1 mutation in which the severities of ocular anterior segment dysgenesis (ASD), myopathy and intracerebral hemorrhage (ICH) were dependent on genetic background. Here, we performed a genetic modifier screen to provide insight into the mechanisms contributing to Gould syndrome pathogenesis and identified a single locus [modifier of Gould syndrome 1 (MoGS1)] on Chromosome 1 that suppressed ASD. A separate screen showed that the same locus ameliorated myopathy. Interestingly, MoGS1 had no effect on ICH, suggesting that this phenotype could be mechanistically distinct. We refined the MoGS1 locus to a 4.3 Mb interval containing 18 protein-coding genes, including Fn1, which encodes the extracellular matrix component fibronectin 1. Molecular analysis showed that the MoGS1 locus increased Fn1 expression, raising the possibility that suppression is achieved through a compensatory extracellular mechanism. Furthermore, we found evidence of increased integrin-linked kinase levels and focal adhesion kinase phosphorylation in Col4a1 mutant mice that is partially restored by the MoGS1 locus, implicating the involvement of integrin signaling. Taken together, our results suggest that tissue-specific mechanistic heterogeneity contributes to the variable expressivity of Gould syndrome and that perturbations in integrin signaling may play a role in ocular and muscular manifestations.

UNILATERAL OPTIC NEURITIS AND CENTRAL RETINAL VASCULITIS DUE TO OCULAR SYPHILIS.

PURPOSE: Report a case of concurrent unilateral optic neuritis and central retinal artery occlusion as the presenting signs of syphilis. METHODS: A case report of a 22-year-old man with progressive unilateral vision loss. RESULTS: With no known previous history of syphilis, genital lesions, or other extraocular manifestations, the patient presented with pain with eye movements and decreased color vision. His vision dramatically worsened after a course of oral steroids. Examination was remarkable for severe right optic disk edema with a macular cherry-red spot and mild posterior uveitis. Magnetic resonance imaging of the orbits with contrast revealed enhancement and enlargement of the distal right optic nerve. Fluorescein angiography demonstrated delayed filling of the right central retinal artery, suggestive of impending central retinal artery occlusion. Syphilis serologies were positive from the serum, and cerebrospinal fluid Venereal Disease Research Laboratory test was reactive, consistent with neurosyphilis. Oral steroids were discontinued and vision improved with 2 weeks of intravenous penicillin. CONCLUSION: This unusual case highlights one of the possible initial presentations of syphilis: unilateral optic neuritis and central retinal artery vasculitis with mild posterior uveitis. The worsening of vision after administration of oral steroids also highlights a potential complication of oral steroid use in the absence of a known etiology of vision loss. A thorough history and examination may be helpful in identifying risk factors for infectious causes, including syphilis, and should prompt additional evaluation.