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Published on: August 15, 2019
Identification of missense MAB21L1 variants in microphthalmia and aniridia
Sarah E Seese1,2, Linda M Reis1, Brett Deml1
1Department of Pediatrics and Children's Research Institute, Medical College of Wisconsin, Children's of Wisconsin, Milwaukee, WI, USA.
Abstract:
Microphthalmia, coloboma, and aniridia are congenital ocular phenotypes with a strong genetic component but often unknown cause. We present a likely causative novel variant in MAB21L1, c.152G>T p.(Arg51Leu), in two family members with microphthalmia and aniridia, as well as novel or rare compound heterozygous variants of uncertain significance, c.184C>T p.(Arg62Cys)/c.-68T>C, and c.658G>C p.(Gly220Arg)/c.*529A>G, in two additional probands with microphthalmia, coloboma and/or cataracts. All variants were predicted as damaging by in silico programs. In vitro studies of coding variants revealed normal subcellular localization but variable stability for the corresponding mutant proteins. In vivo complementation assays using the zebrafish mab21l2 Q48Sfs*5 loss-of-function line demonstrated that though overexpression of wild-type MAB21L1 messenger RNA (mRNA) compensated for the loss of mab21l2, none of the coding variant mRNAs produced a statistically significant rescue, with p.(Arg51Leu) showing the highest degree of functional deficiency. Dominant variants in a close homolog of MAB21L1, MAB21L2, have been associated with microphthalmia and/or coloboma and repeatedly involved the same Arg51 residue, further supporting its pathogenicity. The possible role of p.(Arg62Cys) and p.(Gly220Arg) in microphthalmia is similarly supported by the observed functional defects, with or without an additional impact from noncoding MAB21L1 variants identified in each patient. This study suggests a broader spectrum of MAB21L1-associated disease.
Insights
We identified a novel MAB21L1 gene variant linked to microphthalmia and aniridia. Functional studies confirmed its pathogenicity, suggesting MAB21L1 plays a broader role in congenital eye diseases.
Area of Science:
- Genetics
- Ophthalmology
- Molecular Biology
Background:
- Congenital ocular phenotypes like microphthalmia, coloboma, and aniridia often have a genetic basis, but the causative genes are frequently unknown.
- MAB21L1 is a gene implicated in ocular development, with its homolog MAB21L2 known to cause similar conditions.
Purpose of the Study:
- To investigate the genetic cause of microphthalmia, coloboma, and aniridia in affected individuals.
- To functionally characterize novel variants in the MAB21L1 gene.
Main Methods:
- Genetic sequencing to identify variants in MAB21L1.
- In silico prediction of variant pathogenicity.
- In vitro studies assessing protein stability.
- In vivo complementation assays in zebrafish models.
Main Results:
- A likely causative novel MAB21L1 variant (c.152G>T p.(Arg51Leu)) was identified in two families with microphthalmia and aniridia.
- Additional compound heterozygous variants in MAB21L1 were found in other patients with microphthalmia, coloboma, and/or cataracts.
- Functional studies indicated impaired protein stability and lack of rescue in zebrafish models for the identified variants, particularly p.(Arg51Leu).
Conclusions:
- The study implicates MAB21L1 variants in a spectrum of congenital eye diseases.
- The findings highlight the importance of MAB21L1 in ocular development and suggest a broader disease spectrum than previously recognized.
- The identified variants, especially at the conserved Arg51 residue, are strongly supported as pathogenic.
