The coexistence of MRCS (microcornea, retinal dystrophy, cataract, and posterior staphyloma) syndrome and extremely long axis is rare since microcornea frequently accompanies with diminution of entire anterior segment and occasionally the whole globe. In the case presented here, combination of these two elements were identified, together with XFS (exfoliation syndrome). A 66-year-old Han Chinese woman presented for consultation due to impaired vision which accompanied throughout her entire life span and worsened during the last 2 years. Combination of MRCS syndrome and extremely long axial length was evidently diagnosed in both eyes, with XFS confirmed in her right eye, but mutation screening failed to identify disease-causing sequence variants in some specific genes reported previously, including BEST1 and ARL2. However, likely pathogenic mutations in FBN2 gene were identified. Bilateral cataract phacoemulsification without intraocular lens implantation was performed using scleral tunnel incision and under general anesthesia. At 3-month follow-up, ocular recovery of the patient was satisfactory. The case presented here exhibited rare coexistence of MRCS syndrome, extremely long axis and XFS. The complexity of her ocular abnormalities brought challenges to surgical management, in which multidisciplinary collaboration is often required. Furthermore, the genetic analysis in this case yielded a possible novel candidate gene for MRCS syndrome and provided evidence in support of genetic heterogeneity in this phenotype.

Adenosine diphosphate (ADP)-ribosylation factor-like 2 (ARL2) protein participates in a broad range of cellular processes and acts as a mediator for mutant ARL2BP in cilium-associated retinitis pigmentosa and for mutant HRG4 in mitochondria-related photoreceptor degeneration. However, mutant ARL2 has not been linked to any human disease so far. Here, we identified a de novo variant in ARL2 (c.44G > T, p.R15L) in a Chinese pedigree with MRCS (microcornea, rod-cone dystrophy, cataract, and posterior staphyloma) syndrome through whole-exome sequencing and co-segregation analysis. Co-immunoprecipitation assay and immunoblotting confirmed that the mutant ARL2 protein showed a 62% lower binding affinity for HRG4 while a merely 18% lower binding affinity for ARL2BP. Immunofluorescence images of ARL2 and HRG4 co-localizing with cytochrome c in HeLa cells described their relationship with mitochondria. Further analyses of the mitochondrial respiratory chain and adenosine triphosphate production showed significant abnormalities under an ARL2-mutant condition. Finally, we generated transgenic mice to test the pathogenicity of this variant and observed retinal degeneration complicated with microcornea and cataract that were similar to those in our patients. In conclusion, we uncover ARL2 as a novel candidate gene for MRCS syndrome and suggest a mitochondria-related mechanism of the first ARL2 variant through site-directed mutagenesis studies.