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Beleggia, F.* ; Li, Y.* ; Fan, J.* ; Elcioğlu, N.H.* ; Toker, E.* ; Wieland, T. ; Maumenee, I.H.* ; Akarsu, N.A.* ; Meitinger, T. ; Strom, T.M. ; Lang, R.* ; Wollnik, B.*

CRIM1 haploinsufficiency causes defects in eye development in human and mouse.

Hum. Mol. Genet. 24, 2267-2273 (2015)
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Colobomatous macrophthalmia with microcornea syndrome (MACOM, 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 three generations. Since no shared novel variation was found on the linked haplotype, we performed CNV analysis by comparing the coverage of all exons in the WES data sets of the two patients with the coverage of 26 control exomes. We identified a heterozygous deletion predicted to span 22 kb including exons 14 to 17 of CRIM1 (cysteine rich transmembrane BMP regulator 1). 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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Bone Morphogenetic Proteins; Colobomatous Macrophthalmia; Microcornea Syndrome; Sequencing Data; Optic Fissure; Copy Number; Expression; Cell; Differentiation; Mechanism
Language english
Publication Year 2015
HGF-reported in Year 2015
ISSN (print) / ISBN 0964-6906
e-ISSN 1460-2083
Journal Human Molecular Genetics
Quellenangaben Volume: 24, Issue: 8, Pages: 2267-2273 Article Number: , Supplement: ,
Publisher Oxford University Press
Publishing Place Oxford
Reviewing status Peer reviewed
Institute(s) Institute of Human Genetics (IHG)
POF-Topic(s) 30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
Research field(s) Genetics and Epidemiology
PSP Element(s) G-500700-001
PubMed ID 25561690
DOI 10.1093/hmg/ddu744
WOS ID WOS:000353066200013
Scopus ID 84926430363
Erfassungsdatum 2015-04-08
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