Monoallelic and biallelic mutations in MAB21L2 cause a spectrum of major eye malformations.

TitleMonoallelic and biallelic mutations in MAB21L2 cause a spectrum of major eye malformations.
Publication TypeJournal Article
Year of Publication2014
AuthorsRainger, J, Pehlivan, D, Johansson, S, Bengani, H, Sanchez-Pulido, L, Williamson, KA, Ture, M, Barker, H, Rosendahl, K, Spranger, J, Horn, D, Meynert, A, Floyd, JAB, Prescott, T, Anderson, CA, Rainger, JK, Karaca, E, Gonzaga-Jauregui, C, Jhangiani, S, Muzny, DM, Seawright, A, Soares, DC, Kharbanda, M, Murday, V, Finch, A, Gibbs, RA, van Heyningen, V, Taylor, MS, Yakut, T, Knappskog, PM, Hurles, ME, Ponting, CP, Lupski, JR, Houge, G, FitzPatrick, DR
Corporate Authors,
JournalAm J Hum Genet
Volume94
Issue6
Pagination915-23
Date Published2014 Jun 5
ISSN1537-6605
KeywordsAdult, Alleles, Animals, Anophthalmos, Brain Diseases, Metabolic, Inborn, Coloboma, Corneal Opacity, Exome, Eye Proteins, Female, Gene Expression, HEK293 Cells, Heterozygote, Homozygote, Humans, Intellectual Disability, Intracellular Signaling Peptides and Proteins, Male, Mice, Microcephaly, Microphthalmos, Mutation, Missense, Pedigree, Phenotype, Protein Conformation, Signal Transduction
Abstract

We identified four different missense mutations in the single-exon gene MAB21L2 in eight individuals with bilateral eye malformations from five unrelated families via three independent exome sequencing projects. Three mutational events altered the same amino acid (Arg51), and two were identical de novo mutations (c.151C>T [p.Arg51Cys]) in unrelated children with bilateral anophthalmia, intellectual disability, and rhizomelic skeletal dysplasia. c.152G>A (p.Arg51His) segregated with autosomal-dominant bilateral colobomatous microphthalmia in a large multiplex family. The fourth heterozygous mutation (c.145G>A [p.Glu49Lys]) affected an amino acid within two residues of Arg51 in an adult male with bilateral colobomata. In a fifth family, a homozygous mutation (c.740G>A [p.Arg247Gln]) altering a different region of the protein was identified in two male siblings with bilateral retinal colobomata. In mouse embryos, Mab21l2 showed strong expression in the developing eye, pharyngeal arches, and limb bud. As predicted by structural homology, wild-type MAB21L2 bound single-stranded RNA, whereas this activity was lost in all altered forms of the protein. MAB21L2 had no detectable nucleotidyltransferase activity in vitro, and its function remains unknown. Induced expression of wild-type MAB21L2 in human embryonic kidney 293 cells increased phospho-ERK (pERK1/2) signaling. Compared to the wild-type and p.Arg247Gln proteins, the proteins with the Glu49 and Arg51 variants had increased stability. Abnormal persistence of pERK1/2 signaling in MAB21L2-expressing cells during development is a plausible pathogenic mechanism for the heterozygous mutations. The phenotype associated with the homozygous mutation might be a consequence of complete loss of MAB21L2 RNA binding, although the cellular function of this interaction remains unknown.

DOI10.1016/j.ajhg.2014.05.005
Alternate JournalAm. J. Hum. Genet.
PubMed ID24906020
PubMed Central IDPMC4121478
Grant ListMRC_MC_PC_U127527199 / / Medical Research Council / United Kingdom
U54 HG006542 / HG / NHGRI NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
MRC_MC_PC_U127561093 / / Medical Research Council / United Kingdom
MRC_MC_U127527199 / / Medical Research Council / United Kingdom
MRC_MC_PC_U127597124 / / Medical Research Council / United Kingdom
WT091310 / / Wellcome Trust / United Kingdom
WT100140 / WT / WETP NIH HHS / United States
MRC_MC_U137761446 / / Medical Research Council / United Kingdom