title: C21orf2 is mutated in recessive early-onset retinal dystrophy with macular staphyloma and encodes a protein that localises to the photoreceptor primary cilium.
abstract: OBJECTIVE
  We have noted a phenotype of early-onset retinal dystrophy with macular staphyloma but without high myopia. The aim of this study is to report the underlying genetic mutations and the subcellular localisation of the gene product in the retina.
  
  
  METHODS
  Retrospective case series (2012-2015); immunohistochemical analyses of mammalian retina for in situ protein localisation.
  
  
  RESULTS
  All three probands were first noted to have decreased vision at 3-6 years old which worsened over time. At ages 39, 37 and 12 years old, all had similar retinal findings: dystrophic changes (retinal pigment epithelium mottling, vessel narrowing), macular staphyloma (despite only mild myopia or high hyperopia), and non-recordable electroretinography. All harboured homozygous mutations in C21orf2, a gene recently suggested to be associated with retinal dystrophy but of unknown function. Two had a frameshift deletion c.436_466del (p.Glu146Serfs*6). The third had a missense mutation affecting a highly conserved residue (p.Cys61Tyr) and was short (below the 3rd percentile) and obese (50th percentile for weight despite short stature). Immunohistochemical studies in human, pig and mouse retinas localised C21orf2 protein to the ciliary structures of the photoreceptor cell (the daughter basal body, the centriole adjacent to the basal body, and the connecting cilium).
  
  
  CONCLUSIONS
  This retinal dystrophy phenotype is caused by recessive mutations in C21orf2 and can be considered a retinal ciliopathy as C21orf2 encodes a protein that localises to photoreceptor ciliary structures. The short stature and obesity noted in the youngest girl suggest that for some patients biallelic C21orf2 mutations may result in syndromic ciliopathy.
authors: Division of Pediatric Ophthalmology, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia.
authors: Arif O
authors: AO
authors: Khan
authors: Bioscientia Center for Human Genetics, Ingelheim, Germany.
authors: Tobias
authors: T
authors: Eisenberger
authors: Department of Cell and Matrix Biology, Institute of Zoology, Johannes Gutenberg University of Mainz, Mainz, Germany.
authors: Kerstin
authors: K
authors: Nagel-Wolfrum
authors: Department of Cell and Matrix Biology, Institute of Zoology, Johannes Gutenberg University of Mainz, Mainz, Germany.
authors: Uwe
authors: U
authors: Wolfrum
authors: Bioscientia Center for Human Genetics, Ingelheim, Germany Institute of Human Genetics, University Hospital of Cologne, Cologne, Germany.
authors: Hanno J
authors: HJ
authors: Bolz
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D002648:Child; D003241:Consanguinity; D003598:Cytoskeletal Proteins; D004108:Dilatation, Pathologic; D004596:Electroretinography; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics*; D005808:Genes, Recessive; D006801:Humans; D008279:Magnetic Resonance Imaging; D051379:Mice; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D055212:Photoreceptor Connecting Cilium / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D012160:Retina / Q000473:pathology*; D058499:Retinal Dystrophies / Q000235:genetics*; D012189:Retrospective Studies; D034421:Sus scrofa; D014019:Tissue Donors; D041623:Tomography, Optical Coherence
chemical_list: C111475:CFAP410 protein, human; D003598:Cytoskeletal Proteins; D011506:Proteins
keywords: Degeneration; Dystrophy; Genetics; Retina