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

Am J Hum Genet. 2014 Jun 5;94(6):915-23. doi: 10.1016/j.ajhg.2014.05.005.

Joe Rainger ¹, Davut Pehlivan ², Stefan Johansson ³, Hemant Bengani ¹, Luis Sanchez-Pulido ⁴, Kathleen A Williamson ¹, Mehmet Ture ⁵, Heather Barker ⁶, Karen Rosendahl ⁷, Jürgen Spranger ⁸, Denise Horn ⁹, Alison Meynert ¹, James A B Floyd ¹⁰, Trine Prescott ¹¹, Carl A Anderson ¹⁰, Jacqueline K Rainger ¹, Ender Karaca ², Claudia Gonzaga-Jauregui ², Shalini Jhangiani ¹², Donna M Muzny ¹², Anne Seawright ¹, Dinesh C Soares ¹³, Mira Kharbanda ¹⁴, Victoria Murday ¹⁴, Andrew Finch ⁶, UK10K, Baylor-Hopkins Center for Mendelian Genomics, Richard A Gibbs ¹⁵, Veronica van Heyningen ¹, Martin S Taylor ¹, Tahsin Yakut ⁵, Per M Knappskog ³, Matthew E Hurles ¹⁰, Chris P Ponting ⁴, James R Lupski ¹⁵, Gunnar Houge ¹⁶, David R FitzPatrick ¹⁷

Affiliations

1 Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics and Molecular Medicine, Edinburgh EH4 2XU, UK.
2 Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, 604B, Houston, TX 77030, USA.
3 Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Jonas Liesvei 65, 5021 Bergen, Norway; Department of Clinical Science, University of Bergen, 5020 Bergen, Norway.
4 Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy, and Genetics, University of Oxford, South Parks Road, Oxford OX1 3PT, UK.
5 Department of Medical Genetics, University of Uludag, 16120 Bursa, Turkey.
6 Edinburgh Cancer Research Centre, Medical Research Council Institute of Genetics and Molecular Medicine, Edinburgh EH4 2XU, UK.
7 Paediatric Radiology Department, Haukeland University Hospital, 5021 Bergen, Norway.
8 Im Fuchsberg 14, D76547 Sinzheim, Germany.
9 Institut für Medizinische Genetik, Charité Campus Virchow-Klinikum, 13353 Berlin, Germany.
10 Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
11 Medical Genetics, Oslo University Hospital, 0424 Oslo, Norway.
12 Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, MS BCM225, Houston, TX 77030, USA.
13 Centre for Genomics and Experimental Medicine, Medical Research Council Institute Genetics and Molecular Medicine, Edinburgh EH4 2XU, UK.
14 Clinical Genetics, Southern General Hospital, Glasgow G51 4TF, UK.
15 Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, 604B, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, MS BCM225, Houston, TX 77030, USA.
16 Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Jonas Liesvei 65, 5021 Bergen, Norway.
17 Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics and Molecular Medicine, Edinburgh EH4 2XU, UK. Electronic address: david.fitzpatrick@igmm.ed.ac.uk.

PMID: 24906020 DOI: 10.1016/j.ajhg.2014.05.005

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.

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