Imperial College London
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Dr Sek-Shir Cheong

Faculty of Medicine, National Heart & Lung Institute

Research Associate
 
 
 
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Contact

 

sek-shir.cheong

 
 
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Location

 

Desk 10Sir Alexander Fleming BuildingSouth Kensington Campus

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Summary

 

Publications

Citation

BibTex format

@article{Cheong:2016:10.1016/j.ajhg.2016.09.022,
author = {Cheong, S-S and Hentschel, L and Davidson, AE and Gerrelli, D and Davie, R and Rizzo, R and Pontikos, N and Plagnol, V and Moore, AT and Sowden, JC and Michaelides, M and Snead, M and Tuft, SJ and Hardcastle, AJ},
doi = {10.1016/j.ajhg.2016.09.022},
journal = {American Journal of Human Genetics},
pages = {1338--1352},
title = {Mutations in CPAMD8 cause a unique form of autosomal-recessive anterior segment dysgenesis},
url = {http://dx.doi.org/10.1016/j.ajhg.2016.09.022},
volume = {99},
year = {2016}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Anterior segment dysgeneses (ASDs) comprise a spectrum of developmental disorders affecting the anterior segment of the eye. Here, we describe three unrelated families affected by a previously unclassified form of ASD. Shared ocular manifestations include bilateral iris hypoplasia, ectopia lentis, corectopia, ectropion uveae, and cataracts. Whole-exome sequencing and targeted Sanger sequencing identified mutations in CPAMD8 (C3 and PZP-like alpha-2-macroglobulin domain-containing protein 8) as the cause of recessive ASD in all three families. A homozygous missense mutation in the evolutionarily conserved alpha-2-macroglobulin (A2M) domain of CPAMD8, c.4351T>C (p. Ser1451Pro), was identified in family 1. In family 2, compound heterozygous frameshift, c.2352_2353insC (p.Arg785Glnfs∗23), and splice-site, c.4549-1G>A, mutations were identified. Two affected siblings in the third family were compound heterozygous for splice-site mutations c.700+1G>T and c.4002+1G>A. CPAMD8 splice-site mutations caused aberrant pre-mRNA splicing in vivo or in vitro. Intriguingly, our phylogenetic analysis revealed rodent lineage-specific CPAMD8 deletion, precluding a developmental expression study in mice. We therefore investigated the spatiotemporal expression of CPAMD8 in the developing human eye. RT-PCR and in situ hybridization revealed CPAMD8 expression in the lens, iris, cornea, and retina early in development, including strong expression in the distal tips of the retinal neuroepithelium that form the iris and ciliary body, thus correlating CPAMD8 expression with the affected tissues. Our study delineates a unique form of recessive ASD and defines a role for CPAMD8, a protein of unknown function, in anterior segment development, implying another pathway for the pathogenicity of ASD.
AU  - Cheong,S-S
AU  - Hentschel,L
AU  - Davidson,AE
AU  - Gerrelli,D
AU  - Davie,R
AU  - Rizzo,R
AU  - Pontikos,N
AU  - Plagnol,V
AU  - Moore,AT
AU  - Sowden,JC
AU  - Michaelides,M
AU  - Snead,M
AU  - Tuft,SJ
AU  - Hardcastle,AJ
DO  - 10.1016/j.ajhg.2016.09.022
EP  - 1352
PY  - 2016///
SN  - 0002-9297
SP  - 1338
TI  - Mutations in CPAMD8 cause a unique form of autosomal-recessive anterior segment dysgenesis
T2  - American Journal of Human Genetics
UR  - http://dx.doi.org/10.1016/j.ajhg.2016.09.022
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000389148600009&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - https://www.sciencedirect.com/science/article/pii/S0002929716304359?via%3Dihub
UR  - http://hdl.handle.net/10044/1/95065
VL  - 99
ER  -
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