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

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Abstract

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
Volume7
Issue number7
DOIs
Publication statusPublished - Jul 1998

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Retinoschisis
Mutation
Missense Mutation
Proteins
Exons
Information Storage and Retrieval
Protein Folding

ASJC Scopus subject areas

  • Genetics

Cite this

Den Dunnen, J. T., Kraayenbrink, T., Van Schooneveld, M., Van Vosse, E. D., De Jong, P. T. V. M., Ten Brink, J. B., ... Yates, J. R. W. (1998). Functional implications of the spectrum of mutations found in 234 cases with X-linked juvenile retinoschisis (XLRS). Human Molecular Genetics, 7(7), 1185-1192. https://doi.org/10.1093/hmg/7.7.1185

Functional implications of the spectrum of mutations found in 234 cases with X-linked juvenile retinoschisis (XLRS). / Den Dunnen, Johan T.; Kraayenbrink, Thirsa; Van Schooneveld, Mary; Van Vosse, Esther De; De Jong, Paulus T V M; Ten Brink, Jacoline B.; Schuurman, Ellen; Tijmes, Nel; Van Ommen, Gen Jan B; Bergen, Arthur A B; Andolfi, Grazia; Montini, Eugenio; Li, Yün; Oudet, Claudine; Bolz, Hanno; Kaplan, Josselyne; Orth, Ulrike; Gal, Andreas; Hanauer, Andre; Bardelli, Anna Maria; Ayuso, Carmen; Bitoun, Pierre; Ventruto, Valerio; Dallapiccola, Bruno; Ballabio, Andrea; Franco, Brunella; Hiriyanna, K. T.; Bingham, Eve L.; McHenry, Christina; Pawar, Hemant; Coats, Caraline; Darga, Thomas; Richards, Julia E.; Sieving, Paul A.; Huopaniemi, Laura; Rantala, Anne; Rosenberg, Thomas; Dahl, Niklas; Wright, Alan; De La Chapelle, Albert; Alitalo, Tiina; Lenzner, Steffen; Brunner, Bodo; Feil, Silke; Niesler, Beate; Schulz, Ute; Pinckers, Alfred; Blankennagel, Anita; Ruether, Klaus; Kellner, Ulrich; Rappold, Gudrun; Ropers, H. Hilger; Kalscheuer, Vera; Berger, Wolfgang; Trump, Dorothy; Walpole, Susannah M.; Nicolaou, Alexia; Gaythor, Simon A.; Pimenides, Dimitris; George, Nick D L; Moore, Anthony T.; Yates, John R W.

In: Human Molecular Genetics, Vol. 7, No. 7, 07.1998, p. 1185-1192.

Research output: Contribution to journalArticle

Den Dunnen, JT, Kraayenbrink, T, Van Schooneveld, M, Van Vosse, ED, De Jong, PTVM, Ten Brink, JB, Schuurman, E, Tijmes, N, Van Ommen, GJB, Bergen, AAB, Andolfi, G, Montini, E, Li, Y, Oudet, C, Bolz, H, Kaplan, J, Orth, U, Gal, A, Hanauer, A, Bardelli, AM, Ayuso, C, Bitoun, P, Ventruto, V, Dallapiccola, B, Ballabio, A, Franco, B, Hiriyanna, KT, Bingham, EL, McHenry, C, Pawar, H, Coats, C, Darga, T, Richards, JE, Sieving, PA, Huopaniemi, L, Rantala, A, Rosenberg, T, Dahl, N, Wright, A, De La Chapelle, A, Alitalo, T, Lenzner, S, Brunner, B, Feil, S, Niesler, B, Schulz, U, Pinckers, A, Blankennagel, A, Ruether, K, Kellner, U, Rappold, G, Ropers, HH, Kalscheuer, V, Berger, W, Trump, D, Walpole, SM, Nicolaou, A, Gaythor, SA, Pimenides, D, George, NDL, Moore, AT & Yates, JRW 1998, 'Functional implications of the spectrum of mutations found in 234 cases with X-linked juvenile retinoschisis (XLRS)', Human Molecular Genetics, vol. 7, no. 7, pp. 1185-1192. https://doi.org/10.1093/hmg/7.7.1185
Den Dunnen JT, Kraayenbrink T, Van Schooneveld M, Van Vosse ED, De Jong PTVM, Ten Brink JB et al. Functional implications of the spectrum of mutations found in 234 cases with X-linked juvenile retinoschisis (XLRS). Human Molecular Genetics. 1998 Jul;7(7):1185-1192. https://doi.org/10.1093/hmg/7.7.1185
Den Dunnen, Johan T. ; Kraayenbrink, Thirsa ; Van Schooneveld, Mary ; Van Vosse, Esther De ; De Jong, Paulus T V M ; Ten Brink, Jacoline B. ; Schuurman, Ellen ; Tijmes, Nel ; Van Ommen, Gen Jan B ; Bergen, Arthur A B ; Andolfi, Grazia ; Montini, Eugenio ; Li, Yün ; Oudet, Claudine ; Bolz, Hanno ; Kaplan, Josselyne ; Orth, Ulrike ; Gal, Andreas ; Hanauer, Andre ; Bardelli, Anna Maria ; Ayuso, Carmen ; Bitoun, Pierre ; Ventruto, Valerio ; Dallapiccola, Bruno ; Ballabio, Andrea ; Franco, Brunella ; Hiriyanna, K. T. ; Bingham, Eve L. ; McHenry, Christina ; Pawar, Hemant ; Coats, Caraline ; Darga, Thomas ; Richards, Julia E. ; Sieving, Paul A. ; Huopaniemi, Laura ; Rantala, Anne ; Rosenberg, Thomas ; Dahl, Niklas ; Wright, Alan ; De La Chapelle, Albert ; Alitalo, Tiina ; Lenzner, Steffen ; Brunner, Bodo ; Feil, Silke ; Niesler, Beate ; Schulz, Ute ; Pinckers, Alfred ; Blankennagel, Anita ; Ruether, Klaus ; Kellner, Ulrich ; Rappold, Gudrun ; Ropers, H. Hilger ; Kalscheuer, Vera ; Berger, Wolfgang ; Trump, Dorothy ; Walpole, Susannah M. ; Nicolaou, Alexia ; Gaythor, Simon A. ; Pimenides, Dimitris ; George, Nick D L ; Moore, Anthony T. ; Yates, John R W. / Functional implications of the spectrum of mutations found in 234 cases with X-linked juvenile retinoschisis (XLRS). In: Human Molecular Genetics. 1998 ; Vol. 7, No. 7. pp. 1185-1192.
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abstract = "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.",
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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

AU - Rappold, Gudrun

AU - Ropers, H. Hilger

AU - Kalscheuer, Vera

AU - Berger, Wolfgang

AU - Trump, Dorothy

AU - Walpole, Susannah M.

AU - Nicolaou, Alexia

AU - Gaythor, Simon A.

AU - Pimenides, Dimitris

AU - George, Nick D L

AU - Moore, Anthony T.

AU - Yates, John R W

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.

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