Monoallelic variants resulting in substitutions of MAB21L1 Arg51 Cause Aniridia and microphthalmia.
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 mono...
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Public Library of Science (PLoS)
2022-01-01
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| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0268149&type=printable |
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| author | Hildegard Nikki Hall Hemant Bengani Robert B Hufnagel Giuseppe Damante Morad Ansari Joseph A Marsh Graeme R Grimes Alex von Kriegsheim David Moore Lisa McKie Jamalia Rahmat Catia Mio Moira Blyth Wee Teik Keng Lily Islam Meriel McEntargart Marcel M Mannens Veronica Van Heyningen Joe Rainger Brian P Brooks David R FitzPatrick |
| author_facet | Hildegard Nikki Hall Hemant Bengani Robert B Hufnagel Giuseppe Damante Morad Ansari Joseph A Marsh Graeme R Grimes Alex von Kriegsheim David Moore Lisa McKie Jamalia Rahmat Catia Mio Moira Blyth Wee Teik Keng Lily Islam Meriel McEntargart Marcel M Mannens Veronica Van Heyningen Joe Rainger Brian P Brooks David R FitzPatrick |
| author_sort | Hildegard Nikki Hall |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-9d06bad8b8e446029dee31c9786b024b |
| institution | Kabale University |
| issn | 1932-6203 |
| language | English |
| publishDate | 2022-01-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS ONE |
| spelling | doaj-art-9d06bad8b8e446029dee31c9786b024b2025-01-24T05:31:11ZengPublic Library of Science (PLoS)PLoS ONE1932-62032022-01-011711e026814910.1371/journal.pone.0268149Monoallelic variants resulting in substitutions of MAB21L1 Arg51 Cause Aniridia and microphthalmia.Hildegard Nikki HallHemant BenganiRobert B HufnagelGiuseppe DamanteMorad AnsariJoseph A MarshGraeme R GrimesAlex von KriegsheimDavid MooreLisa McKieJamalia RahmatCatia MioMoira BlythWee Teik KengLily IslamMeriel McEntargartMarcel M MannensVeronica Van HeyningenJoe RaingerBrian P BrooksDavid R FitzPatrickClassical 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.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0268149&type=printable |
| spellingShingle | Hildegard Nikki Hall Hemant Bengani Robert B Hufnagel Giuseppe Damante Morad Ansari Joseph A Marsh Graeme R Grimes Alex von Kriegsheim David Moore Lisa McKie Jamalia Rahmat Catia Mio Moira Blyth Wee Teik Keng Lily Islam Meriel McEntargart Marcel M Mannens Veronica Van Heyningen Joe Rainger Brian P Brooks David R FitzPatrick Monoallelic variants resulting in substitutions of MAB21L1 Arg51 Cause Aniridia and microphthalmia. PLoS ONE |
| title | Monoallelic variants resulting in substitutions of MAB21L1 Arg51 Cause Aniridia and microphthalmia. |
| title_full | Monoallelic variants resulting in substitutions of MAB21L1 Arg51 Cause Aniridia and microphthalmia. |
| title_fullStr | Monoallelic variants resulting in substitutions of MAB21L1 Arg51 Cause Aniridia and microphthalmia. |
| title_full_unstemmed | Monoallelic variants resulting in substitutions of MAB21L1 Arg51 Cause Aniridia and microphthalmia. |
| title_short | Monoallelic variants resulting in substitutions of MAB21L1 Arg51 Cause Aniridia and microphthalmia. |
| title_sort | monoallelic variants resulting in substitutions of mab21l1 arg51 cause aniridia and microphthalmia |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0268149&type=printable |
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