TY - JOUR
T1 - Monoallelic variants resulting in substitutions of MAB21L1 Arg51 Cause Aniridia and microphthalmia
AU - Hall, Hildegard Nikki
AU - Bengani, Hemant
AU - Hufnagel, Robert B.
AU - Damante, Giuseppe
AU - Ansari, Morad
AU - Marsh, Joseph A.
AU - Grimes, Graeme R.
AU - von Kriegsheim, Alex
AU - Moore, David
AU - McKie, Lisa
AU - Rahmat, Jamalia
AU - Mio, Catia
AU - Blyth, Moira
AU - Keng, Wee Teik
AU - Islam, Lily
AU - McEntargart, Meriel
AU - Mannens, Marcel M.
AU - van Heyningen, Veronica
AU - Rainger, Joe
AU - Brooks, Brian P.
AU - FitzPatrick, David R.
N1 - Funding Information: Funding:H.N.H.isfundedbyaWellcomeTrust fellowship(205171_Z_16_Z).D.R.F.issupported byMedicalResearchCouncil(MRC)University UnitprogramgrantawardedtotheUniversityof Edinburgh.FundingforUK10Kwasprovidedby WellcomeunderawardWT091310. Publisher Copyright: Copyright: © This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
PY - 2022/11/1
Y1 - 2022/11/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85142918853&partnerID=8YFLogxK
U2 - https://doi.org/10.1371/journal.pone.0268149
DO - https://doi.org/10.1371/journal.pone.0268149
M3 - Article
C2 - 36413568
SN - 1932-6203
VL - 17
JO - PLOS ONE
JF - PLOS ONE
IS - 11 November
M1 - e0268149
ER -