title: Monoallelic and biallelic mutations in MAB21L2 cause a spectrum of major eye malformations.
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.
authors.affiliation: Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics and Molecular Medicine, Edinburgh EH4 2XU, UK.
authors.forename: Joe
authors.initials: J
authors.lastname: Rainger
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, 604B, Houston, TX 77030, USA.
authors.forename: Davut
authors.initials: D
authors.lastname: Pehlivan
authors.affiliation: 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.
authors.forename: Stefan
authors.initials: S
authors.lastname: Johansson
authors.affiliation: Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics and Molecular Medicine, Edinburgh EH4 2XU, UK.
authors.forename: Hemant
authors.initials: H
authors.lastname: Bengani
authors.affiliation: Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy, and Genetics, University of Oxford, South Parks Road, Oxford OX1 3PT, UK.
authors.forename: Luis
authors.initials: L
authors.lastname: Sanchez-Pulido
authors.affiliation: Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics and Molecular Medicine, Edinburgh EH4 2XU, UK.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Williamson
authors.affiliation: Department of Medical Genetics, University of Uludag, 16120 Bursa, Turkey.
authors.forename: Mehmet
authors.initials: M
authors.lastname: Ture
authors.affiliation: Edinburgh Cancer Research Centre, Medical Research Council Institute of Genetics and Molecular Medicine, Edinburgh EH4 2XU, UK.
authors.forename: Heather
authors.initials: H
authors.lastname: Barker
authors.affiliation: Paediatric Radiology Department, Haukeland University Hospital, 5021 Bergen, Norway.
authors.forename: Karen
authors.initials: K
authors.lastname: Rosendahl
authors.affiliation: Im Fuchsberg 14, D76547 Sinzheim, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Spranger
authors.affiliation: Institut für Medizinische Genetik, Charité Campus Virchow-Klinikum, 13353 Berlin, Germany.
authors.forename: Denise
authors.initials: D
authors.lastname: Horn
authors.affiliation: Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics and Molecular Medicine, Edinburgh EH4 2XU, UK.
authors.forename: Alison
authors.initials: A
authors.lastname: Meynert
authors.affiliation: Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: James A B
authors.initials: JA
authors.lastname: Floyd
authors.affiliation: Medical Genetics, Oslo University Hospital, 0424 Oslo, Norway.
authors.forename: Trine
authors.initials: T
authors.lastname: Prescott
authors.affiliation: Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Carl A
authors.initials: CA
authors.lastname: Anderson
authors.affiliation: Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics and Molecular Medicine, Edinburgh EH4 2XU, UK.
authors.forename: Jacqueline K
authors.initials: JK
authors.lastname: Rainger
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, 604B, Houston, TX 77030, USA.
authors.forename: Ender
authors.initials: E
authors.lastname: Karaca
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, 604B, Houston, TX 77030, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Gonzaga-Jauregui
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, MS BCM225, Houston, TX 77030, USA.
authors.forename: Shalini
authors.initials: S
authors.lastname: Jhangiani
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, MS BCM225, Houston, TX 77030, USA.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Muzny
authors.affiliation: Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics and Molecular Medicine, Edinburgh EH4 2XU, UK.
authors.forename: Anne
authors.initials: A
authors.lastname: Seawright
authors.affiliation: Centre for Genomics and Experimental Medicine, Medical Research Council Institute Genetics and Molecular Medicine, Edinburgh EH4 2XU, UK.
authors.forename: Dinesh C
authors.initials: DC
authors.lastname: Soares
authors.affiliation: Clinical Genetics, Southern General Hospital, Glasgow G51 4TF, UK.
authors.forename: Mira
authors.initials: M
authors.lastname: Kharbanda
authors.affiliation: Clinical Genetics, Southern General Hospital, Glasgow G51 4TF, UK.
authors.forename: Victoria
authors.initials: V
authors.lastname: Murday
authors.affiliation: Edinburgh Cancer Research Centre, Medical Research Council Institute of Genetics and Molecular Medicine, Edinburgh EH4 2XU, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Finch
authors.affiliation: 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.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.affiliation: Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics and Molecular Medicine, Edinburgh EH4 2XU, UK.
authors.forename: Veronica
authors.initials: V
authors.lastname: van Heyningen
authors.affiliation: Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics and Molecular Medicine, Edinburgh EH4 2XU, UK.
authors.forename: Martin S
authors.initials: MS
authors.lastname: Taylor
authors.affiliation: Department of Medical Genetics, University of Uludag, 16120 Bursa, Turkey.
authors.forename: Tahsin
authors.initials: T
authors.lastname: Yakut
authors.affiliation: 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.
authors.forename: Per M
authors.initials: PM
authors.lastname: Knappskog
authors.affiliation: Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Hurles
authors.affiliation: Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy, and Genetics, University of Oxford, South Parks Road, Oxford OX1 3PT, UK.
authors.forename: Chris P
authors.initials: CP
authors.lastname: Ponting
authors.affiliation: 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.
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.affiliation: Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Jonas Liesvei 65, 5021 Bergen, Norway.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Houge
authors.affiliation: 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.
authors.forename: David R
authors.initials: DR
authors.lastname: FitzPatrick
mesh_terms: D000328:Adult; D000483:Alleles; D000818:Animals; D000853:Anophthalmos / Q000235:genetics*; D020739:Brain Diseases, Metabolic, Inborn / Q000235:genetics; D003103:Coloboma / Q000235:genetics; D003318:Corneal Opacity / Q000235:genetics; D059472:Exome; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D057809:HEK293 Cells; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008831:Microcephaly / Q000235:genetics; D008850:Microphthalmos / Q000235:genetics; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D011487:Protein Conformation; D015398:Signal Transduction
chemical_list: D005136:Eye Proteins; D047908:Intracellular Signaling Peptides and Proteins; C000589992:MAB21L2 protein, human; C493284:Mab21l2 protein, mouse