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.
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 called Gould syndrome which can affect any organ but typically involves the cerebral vasculature, eyes, kidneys and skeletal muscles. 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.
Agenesis of the corpus callosum (ACC), a failure of the corpus callosum to develop, is linked to over 50 congenital syndromes. One syndrome which exhibits ACC as a symptom is Temtamy Syndrome, which also presents with craniofacial abnormalities, ocular colobomata, and mild mental retardation. Studies of some of these cases have provided possible candidate genes which may play a role in the etiology of the disorder. Transmembrane tetratricopeptide protein 4 (TMTC4) and Ankyrin repeat and MYND domain containing protein 1 (ANKMY1) were both identified as candidate genes through chromosomal analysis of individuals affected with Temtamy Syndrome. A yeast two‐hybrid protein trap was performed for both of these protein products, and interaction partners for each were identified. Fourteen protein‐coding sequences were identified as interaction partners for Tmtc4, and five protein‐coding sequences were identified as partners for Ankmy1. Only three of the proteins interacting with Tmtc4 were linked to embryonic brain development, and none of the five Ankmy1 interactors have known roles in brain development. The three interacting proteins found were Zfhx4, which regulates neural differentiation, Wntless, a member of the Wnt family and integral Wnt regulator, and C3G, a guanine exchange factor in the Ras pathway which regulates neural precursor population and neuron migration in the cerebral cortex. Future work should confirm these interactions in brain tissue, as well as investigate the effects of the aberrant forms of Tmtc4 on these interactions. These findings could provide much insight into the etiology of Temtamy Syndrome, and ultimately bring us closer to understanding the mechanisms of ACC.
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