Monoallelic variants resulting in substitutions of MAB21L1 Arg51 Cause Aniridia and microphthalmia.
Monoallelic variants resulting in substitutions of MAB21L1 Arg51 Cause Aniridia and microphthalmia.
复制标题
DOI：
10.1371/journal.pone.0268149
复制
发表时间：
2022
期刊：
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
--
作者：
经典无虹膜是一种先天性和进行性全眼疾病，几乎完全由PAX 6基因座的杂合功能丧失变体引起。我们报告了来自5个严重无虹膜和/或小眼症（没有检测到PAX 6突变）的家庭的9名个体，这些个体具有改变MAB 21 L1的Arg 51密码子的ultrarare单等位基因错义变体。这些突变发生在3/5个家庭中，其余家庭与常染色体显性遗传相容。携带p.Arg51Leu突变的小鼠在杂合子动物中表现出高度渗透性视盘异常，在纯合子动物中表现出严重的小眼症。MAB 21 L2是MAB 21 L1的同源物，其相同密码子（Arg 51）的取代可导致人类和小鼠严重的眼部和骨骼畸形。MAB 21 L1的预测的核苷酸转移酶功能不能使用纯化的蛋白质与各种核苷酸底物和寡核苷酸激活剂证明。GFP标记的野生型和突变型MAB 21 L1在人细胞中的诱导表达仅引起适度的转录变化。免疫沉淀蛋白质的质谱分析显示，突变型和野生型MAB 21 L1均与PAX 6的已知调节因子（MEIS 1、MEIS 2和PBX 1）和poly（A）RNA结合蛋白相关。Arg 51取代减少了野生型MAB 21 L1与TBL 1XR 1（NCoR复合物的一种组分）的结合。我们发现与MSI 2/Musashi-2（一种对许多不同发育途径有影响的RNA结合蛋白）的突变特异性相互作用的证据有限。鉴于MAB 21 L1中的双等位基因功能丧失变体导致较温和的眼睛表型，我们认为Arg 51改变的单等位基因变体最可能通过功能获得机制扰乱眼睛发育。
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.
登录
查看更多内容
影响因子：
3.5
作者：
Bruel, A. -L.;Masurel-Paulet, A.;Thevenon, J.
通讯作者：
Thevenon, J.
影响因子：
9.7
作者：
Douchi, Daisuke;Ohtsuka, Hideo;Unno, Michiaki
通讯作者：
Unno, Michiaki
影响因子：
2.1
作者：
Inoue, Masashi;Kamachi, Yusuke;Kondoh, Hisato
通讯作者：
Kondoh, Hisato
影响因子：
64.8
作者：
HILL, RE;FAVOR, J;VANHEYNINGEN, V
通讯作者：
VANHEYNINGEN, V
影响因子：
4.4
作者：
Cox, Juergen;Neuhauser, Nadin;Mann, Matthias
通讯作者：
Mann, Matthias