title: CRIM1 haploinsufficiency causes defects in eye development in human and mouse.
abstract: Colobomatous macrophthalmia with microcornea syndrome (MACOM, Online Mendelian Inheritance in Man (OMIM) 602499) is an autosomal dominantly inherited malformation of the eye, which is characterized by microcornea with increased axial length, coloboma of the iris and of the optic disc, and severe myopia. We performed whole-exome sequencing (WES) in two affected individuals from the 2p23-p16-linked MACOM family, which includes 13 affected individuals in 3 generations. As no shared novel variation was found on the linked haplotype, we performed copy number variation (CNV) analysis by comparing the coverage of all exons in the WES data sets of the 2 patients with the coverage of 26 control exomes. We identified a heterozygous deletion predicted to span 22 kb including exons 14-17 of CRIM1 (cysteine-rich transmembrane bone morphogenetic protein (BMP) regulator 1). Quantitative PCR (qPCR) analysis confirmed the deletion, which was present in 11 affected individuals. Split-read analysis of WES data followed by breakpoint PCR and Sanger sequencing determined both breakpoints flanked by a 4-bp microhomology (CTTG). In the mouse, Crim1 is a growth-factor-binding protein with pleiotropic roles in the development of multiple organs, including the eye. To investigate the role of Crim1 during eye development in mice, we crossed a Crim1(flox) mouse line with the Ap2α-cre mouse line, which expresses Cre in the head surface ectoderm. Strikingly, we observed alterations of eye development in homozygous mice leading to severe anatomical and morphological changes overlapping with the anomalies observed in MACOM patients. Taken together, these findings identify CRIM1 as the causative gene for MACOM syndrome and emphasize the importance of CRIM1 in eye development.
authors.affiliation: Institute of Human Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
authors.forename: Filippo
authors.initials: F
authors.lastname: Beleggia
authors.affiliation: Institute of Human Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
authors.forename: Yun
authors.initials: Y
authors.lastname: Li
authors.affiliation: Division of Pediatric Ophthalmology and Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Jieqing
authors.initials: J
authors.lastname: Fan
authors.affiliation: Department of Pediatric Genetics.
authors.forename: Nursel H
authors.initials: NH
authors.lastname: Elcioğlu
authors.affiliation: Department of Ophtalmology, Marmara University Medical Faculty, Istanbul, Turkey.
authors.forename: Ebru
authors.initials: E
authors.lastname: Toker
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wieland
authors.affiliation: Illinois Eye and Ear Infirmary, Illinois University, College of Medicine at Chicago, Chicago, IL, USA.
authors.forename: Irene H
authors.initials: IH
authors.lastname: Maumenee
authors.affiliation: Department of Medical Genetics, Gene Mapping Laboratory, Hacettepe University Medical Faculty, Ankara, Turkey and.
authors.forename: Nurten A
authors.initials: NA
authors.lastname: Akarsu
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany, Institute of Human Genetics, Technische Universität München, Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany, Institute of Human Genetics, Technische Universität München, Munich, Germany.
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.affiliation: Division of Pediatric Ophthalmology and Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Lang
authors.affiliation: Institute of Human Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany, bwollnik@uni-koeln.de.
authors.forename: Bernd
authors.initials: B
authors.lastname: Wollnik
mesh_terms: D000328:Adult; D000818:Animals; D001483:Base Sequence; D052004:Bone Morphogenetic Protein Receptors / Q000235:genetics / Q000378:metabolism*; D003316:Corneal Diseases / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D056915:DNA Copy Number Variations; D005091:Exons; D005123:Eye / Q000033:anatomy & histology / Q000254:growth & development* / Q000378:metabolism; D005124:Eye Abnormalities / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D057895:Haploinsufficiency; D006720:Homozygote; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D010375:Pedigree; D055815:Young Adult
chemical_list: C486175:CRIM1 protein, human; C518411:Crim1 protein, mouse; D008565:Membrane Proteins; D052004:Bone Morphogenetic Protein Receptors