PUBLICATION
Identification of missense MAB21L1 variants in microphthalmia and aniridia
- Authors
- Seese, S.E., Reis, L.M., Deml, B., Griffith, C., Reich, A., Jamieson, R.V., Semina, E.V.
- ID
- ZDB-PUB-210512-10
- Date
- 2021
- Source
- Human Mutation 42(7): 877-890 (Journal)
- Registered Authors
- Semina, Elena
- Keywords
- MAB21L1, aniridia, coloboma, microphthalmia, rescue
- MeSH Terms
-
- Animals
- Aniridia*/genetics
- Coloboma*/genetics
- Eye Proteins
- Homeodomain Proteins/genetics
- Humans
- Intracellular Signaling Peptides and Proteins
- Microphthalmos*/genetics
- Zebrafish/genetics
- Zebrafish Proteins/genetics
- PubMed
- 33973683 Full text @ Hum. Mutat.
Citation
Seese, S.E., Reis, L.M., Deml, B., Griffith, C., Reich, A., Jamieson, R.V., Semina, E.V. (2021) Identification of missense MAB21L1 variants in microphthalmia and aniridia. Human Mutation. 42(7):877-890.
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 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 mab21l2Q48Sfs*5 loss-of-function line demonstrated that while overexpression of wild-type MAB21L1 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 non-coding MAB21L1 variants identified in each patient. This study suggests a broader spectrum of MAB21L1-associated disease. This article is protected by copyright. All rights reserved.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping