Monoallelic and Biallelic Mutations in MAB21L2 Cause a Spectrum of Major Eye Malformations

UK10K, Joe Rainger, Davut Pehlivan, Stefan Johansson, Hemant Bengani, Luis Sanchez-Pulido, Kathleen A Williamson, Mehmet Ture, Heather Barker, Karen Rosendahl, Jürgen Spranger, Denise Horn, Alison Meynert, James A B Floyd, Trine Prescott, Carl A Anderson, Jacqueline K Rainger, Ender Karaca, Claudia Gonzaga-Jauregui, Shalini JhangianiDonna M Muzny, Anne Seawright, Dinesh C Soares, Mira Kharbanda, Victoria Murday, Andrew Finch, Richard A Gibbs, Veronica van Heyningen, Martin S Taylor, Tahsin Yakut, Per M Knappskog, Matthew E Hurles, Chris Ponting, James R Lupski, Gunnar Houge, David R FitzPatrick

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.

Original languageEnglish
Pages (from-to)915-923
Number of pages9
JournalAmerican Journal of Human Genetics
Issue number6
Early online date5 Jun 2014
Publication statusPublished - 5 Jun 2014


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