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

Abstract

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 which 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 may 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 show 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.

FKRP directed fibronectin glycosylation: A novel mechanism giving insights into muscular dystrophies?

“…[95] Subsequently, collagens I and II are recruited, and the collagen IV laminin-211 MBM lattice forms. Fibronectin has been shown to impact collagen IV, laminins and their lattice formation, [135][136][137][138] suggesting that aberrant fibronectin function could lead to disruption of this lattice as well. Deficits in this lattice would likely have significant impacts on MBM function throughout development and during homeostasis.…”

TGFβ Signaling Dysregulation May Contribute to COL4A1-Related Glaucomatous Optic Nerve Damage

“…ASD severity was subjectively determined based on the level of iris vessel dilation and tortuosity, pupil dilation, lens opacity, and anterior chamber enlargement, as previously described. 25 , 33 …”

“…Consistent with their ubiquitous expression pattern, mutations in COL4A1 and COL4A2 cause a clinically heterogenous multisystem disorder characterized by cerebrovascular, ocular, renal, and muscular manifestations 20 – 24 that are collectively referred to as Gould syndrome. 25 , 26 After cerebrovascular defects, ocular abnormalities are the most frequent clinical findings in individuals with Gould syndrome. 22 , 23 Ocular features are highly variable and include microphthalmia, ASD, cataracts, strabismus, myopia, retinal artery tortuosity, retinal detachments, optic coloboma, optic nerve hypoplasia, and glaucoma.…”

Central Nervous System and Cardiac Abnormalities in the Setting of a De Novo Heterozygous Col4a1 Variant

“…Phenotypic presentation associated with Col4a1 mutations and Gould Syndrome is variable [3,4]. One study cites tissue-specific mechanistic heterogeneity as a possible cause of variability, with integrin signaling affecting ocular and muscular variability more specifically [7].…”