Functional implications of the spectrum of mutations found in 234 cases with X-linked juvenile retinoschisis (XLRS)

Johan T. Den Dunnen, Thirsa Kraayenbrink, Mary Van Schooneveld, Esther De Van Vosse, Paulus T V M De Jong, Jacoline B. Ten Brink, Ellen Schuurman, Nel Tijmes, Gen Jan B Van Ommen, Arthur A B Bergen, Grazia Andolfi, Eugenio Montini, Yün Li, Claudine Oudet, Hanno Bolz, Josselyne Kaplan, Ulrike Orth, Andreas Gal, Andre Hanauer, Anna Maria BardelliCarmen Ayuso, Pierre Bitoun, Valerio Ventruto, Bruno Dallapiccola, Andrea Ballabio, Brunella Franco, K. T. Hiriyanna, Eve L. Bingham, Christina McHenry, Hemant Pawar, Caraline Coats, Thomas Darga, Julia E. Richards, Paul A. Sieving, Laura Huopaniemi, Anne Rantala, Thomas Rosenberg, Niklas Dahl, Alan Wright, Albert De La Chapelle, Tiina Alitalo, Steffen Lenzner, Bodo Brunner, Silke Feil, Beate Niesler, Ute Schulz, Alfred Pinckers, Anita Blankennagel, Klaus Ruether, Ulrich Kellner, Gudrun Rappold, H. Hilger Ropers, Vera Kalscheuer, Wolfgang Berger, Dorothy Trump, Susannah M. Walpole, Alexia Nicolaou, Simon A. Gaythor, Dimitris Pimenides, Nick D L George, Anthony T. Moore, John R W Yates

Research output: Contribution to journalArticlepeer-review


X-linked retinoschisis (XLRS) is the most common cause of juvenile macular degeneration in males, resulting in vision loss early in life. The gene involved in XLRS was identified recently. It encodes a protein with a disoidin domain, suggested to be involved in cell-cell interactions. We have screened the gene for mutations in 234 familial and sporadic retinoschisis cases and identified 82 different mutations in 214 (91%). Thirty one mutations were found more than once, i.e. 2-10 times, with the exception of the 214G→A mutation which was found in 34 apparently unrelated cases. The origin of the patients, the linkage data and the site of the mutations (mainly CG dinucleotides) indicate that most recurrent mutations had independent origins and thus suggest the existence of a significant new mutation rate in XLRS1. The mutations identified cover the entire spectrum, from small intra-genic deletions (7%), to nonsense (6%), missense (75%), small frameshifting insertions/deletions (6%) and splice site mutations (6%). Since, regardless of the mutation type, no females with a typical RS phenotype were identified, RS seems to be caused by loss-of-function mutations only. Mutations occurred non-randomly, with hotspots at several CG dinudeotides and a C6 stretch. Exons 1-3 contained few, mainly translation-truncating mutations, arguing against an important functional role for this segment of the protein. Exons 4-6, encoding the discoidin domain, contained most, mainly missense mutations. An alignment of 32 discoidin domain proteins was constructed to reveal the consensus sequence and to deduce the functional importance of the missense mutations identified. The mutation analysis revealed a high preponderance of mutations involving or creating cysteine residues, pointing to sites important for the tertiary folding and/or protein function, and highlights several amino acids which may be involved in XLRS1-specific protein-protein interactions. Despite the enormous mutation heterogeneity, patients have relatively uniform clinical manifestations although with great intra-familial variation in age at onset and progression.

Original languageEnglish
Pages (from-to)1185-1192
Number of pages8
JournalHuman Molecular Genetics
Issue number7
Publication statusPublished - Jul 1998

ASJC Scopus subject areas

  • Genetics


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