TY - JOUR
T1 - Functional implications of the spectrum of mutations found in 234 cases with X-linked juvenile retinoschisis (XLRS)
AU - Den Dunnen, Johan T.
AU - Kraayenbrink, Thirsa
AU - Van Schooneveld, Mary
AU - Van Vosse, Esther De
AU - De Jong, Paulus T.V.M.
AU - Ten Brink, Jacoline B.
AU - Schuurman, Ellen
AU - Tijmes, Nel
AU - Van Ommen, Gen Jan B.
AU - Bergen, Arthur A.B.
AU - Andolfi, Grazia
AU - Montini, Eugenio
AU - Li, Yün
AU - Oudet, Claudine
AU - Bolz, Hanno
AU - Kaplan, Josselyne
AU - Orth, Ulrike
AU - Gal, Andreas
AU - Hanauer, Andre
AU - Bardelli, Anna Maria
AU - Ayuso, Carmen
AU - Bitoun, Pierre
AU - Ventruto, Valerio
AU - Dallapiccola, Bruno
AU - Ballabio, Andrea
AU - Franco, Brunella
AU - Hiriyanna, K. T.
AU - Bingham, Eve L.
AU - McHenry, Christina
AU - Pawar, Hemant
AU - Coats, Caraline
AU - Darga, Thomas
AU - Richards, Julia E.
AU - Sieving, Paul A.
AU - Huopaniemi, Laura
AU - Rantala, Anne
AU - Rosenberg, Thomas
AU - Dahl, Niklas
AU - Wright, Alan
AU - De La Chapelle, Albert
AU - Alitalo, Tiina
AU - Lenzner, Steffen
AU - Brunner, Bodo
AU - Feil, Silke
AU - Niesler, Beate
AU - Schulz, Ute
AU - Pinckers, Alfred
AU - Blankennagel, Anita
AU - Ruether, Klaus
AU - Kellner, Ulrich
PY - 1998/7
Y1 - 1998/7
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=7144253129&partnerID=8YFLogxK
U2 - https://doi.org/10.1093/hmg/7.7.1185
DO - https://doi.org/10.1093/hmg/7.7.1185
M3 - Article
C2 - 9618178
SN - 0964-6906
VL - 7
SP - 1185
EP - 1192
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 7
ER -