Monoallelic variants resulting in substitutions of MAB21L1 Arg51 Cause Aniridia and microphthalmia

Abstract

Classical aniridia is a congenital and progressive panocular disorder almost exclusively caused by heterozygous loss-of-function variants at the PAX6 locus. We report nine individuals from five families with severe aniridia and/or microphthalmia (with no detectable PAX6 mutation) with ultrarare monoallelic missense variants altering the Arg51 codon of MAB21L1. These mutations occurred de novo in 3/5 families, with the remaining families being compatible with autosomal dominant inheritance. Mice engineered to carry the p.Arg51Leu change showed a highly-penetrant optic disc anomaly in heterozygous animals with severe microphthalmia in homozygotes. Substitutions of the same codon (Arg51) in MAB21L2, a close homolog of MAB21L1, cause severe ocular and skeletal malformations in humans and mice. The predicted nucleotidyltransferase function of MAB21L1 could not be demonstrated using purified protein with a variety of nucleotide substrates and oligonucleotide activators. Induced expression of GFP-tagged wildtype and mutant MAB21L1 in human cells caused only modest transcriptional changes. Mass spectrometry of immunoprecipitated protein revealed that both mutant and wildtype MAB21L1 associate with transcription factors that are known regulators of PAX6 (MEIS1, MEIS2 and PBX1) and with poly(A) RNA binding proteins. Arg51 substitutions reduce the association of wild-type MAB21L1 with TBL1XR1, a component of the NCoR complex. We found limited evidence for mutation-specific interactions with MSI2/Musashi-2, an RNA-binding proteins with effects on many different developmental pathways. Given that biallelic loss-of-function variants in MAB21L1 result in a milder eye phenotype we suggest that Arg51-altering monoallelic variants most plausibly perturb eye development via a gain-of-function mechanism.

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“…This is not surprising given that papers describing patients with atypical presentations have been only recently published [43]. Furthermore, two MAB21L1 variants were found in our cohort, the hotspot mutation p.Arg51Leu and the previously published p.Phe52Cys (A180 and A97, respectively) [22]. Indeed, MAB21L1 is gaining momentum as a novel gene associated with severe aniridia and/or microphthalmia [22,44].…”

“…Furthermore, two MAB21L1 variants were found in our cohort, the hotspot mutation p.Arg51Leu and the previously published p.Phe52Cys (A180 and A97, respectively) [22]. Indeed, MAB21L1 is gaining momentum as a novel gene associated with severe aniridia and/or microphthalmia [22,44].…”

“…Both dominant and recessive patterns were assessed. Alteration in genes already related to ASD were found, such as a SNV in PITX2 , four different PXDN missense variants in two unrelated patients, a nonsense FZD5 variant in two related patients (A167, mother–A170, son), two variants in the recently discovered MAB21L1 [ 22 ], and three ITPR1 alterations, one in homozygous and two in heterozygous state.…”