Human Molecular Genetics, Vol 7, 1185-1192, Copyright © 1998 by Oxford University Press
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 dinucleotides and a C6stretch. 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.
ARTICLES
Functional implications of the spectrum of mutations found in 234 cases with X-linked juvenile retinoschisis. The Retinoschisis Consortium
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