2. Academic Validation
  3. Mutations in CPAMD8 Cause a Unique Form of Autosomal-Recessive Anterior Segment Dysgenesis

Mutations in CPAMD8 Cause a Unique Form of Autosomal-Recessive Anterior Segment Dysgenesis

  • Am J Hum Genet. 2016 Dec 1;99(6):1338-1352. doi: 10.1016/j.ajhg.2016.09.022.
Sek-Shir Cheong 1,  Lisa Hentschel 2,  Alice E Davidson 1,  Dianne Gerrelli 2,  Rebecca Davie 3,  Roberta Rizzo 4,  Nikolas Pontikos 5,  Vincent Plagnol 5,  Anthony T Moore 6,  Jane C Sowden 2,  Michel Michaelides 7,  Martin Snead 3,  Stephen J Tuft 8,  Alison J Hardcastle 9
Affiliations

Affiliations

  • 1 Institute of Ophthalmology, University College London, London EC1V 9EL, UK.
  • 2 Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.
  • 3 Vitreoretinal Research Group, Cambridge University National Health Service Foundation Trust, Cambridge CB2 0QQ, UK.
  • 4 Moorfields Eye Hospital, London EC1V 2PD, UK.
  • 5 Genetics Institute, University College London, London WC1E 6BT, UK.
  • 6 Institute of Ophthalmology, University College London, London EC1V 9EL, UK; Moorfields Eye Hospital, London EC1V 2PD, UK; Ophthalmology Department, School of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
  • 7 Institute of Ophthalmology, University College London, London EC1V 9EL, UK; Genetics Institute, University College London, London WC1E 6BT, UK.
  • 8 Institute of Ophthalmology, University College London, London EC1V 9EL, UK; Moorfields Eye Hospital, London EC1V 2PD, UK.
  • 9 Institute of Ophthalmology, University College London, London EC1V 9EL, UK. Electronic address: a.hardcastle@ucl.ac.uk.
PMID: 27839872 DOI: 10.1016/j.ajhg.2016.09.022
Abstract

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.

Keywords

A2M/C3; CPAMD8; WES; anterior segment dysgenesis; development; eye; iris; lens.

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