Human Molecular Genetics, Vol 8, 2507-2514, Copyright © 1999 by Oxford University Press
M Attard, G Jean, L Forestier, S Cherqui, W van't Hoff, M Broyer, C Antignac and M Town
Infantile nephropathic cystinosis is a rare, autosomal recessive disease
caused by a defect in the transport of cystine across the lysosomal
membrane and characterized by early onset of renal proximal tubular
dysfunction. Late-onset cystinosis, a rarer form of the disorder, is
characterized by onset of symptoms between 12 and 15 years of age. We
previously characterized the cystinosis gene, CTNS, and identified
pathogenic mutations in patients with infantile nephropathic cystinosis,
including a common, ~65 kb deletion which encompasses exons 1-10. Structure
predictions suggested that the gene product, cystinosin, is a novel
integral lysosomal membrane protein. We now examine the predicted effect of
mutations on this model of cystinosin. In this study, we screened patients
with infantile nephropathic cystinosis, those with late-onset cystinosis
and patients whose phenotype does not fit the classical definitions. We
found 23 different mutations in CTNS; 14 are novel mutations. Out of 25
patients with infantile nephropathic cystinosis, 12 have two severely
truncating mutations, which is consistent with a loss of functional
protein, and 13 have missense or in-frame deletions, which would result in
disruption of transmembrane domains and loss of protein function. Mutations
found in two late-onset patients affect functionally unimportant regions of
cystinosin, which accounts for their milder phenotype. For three patients,
the age of onset of cystinosis was <7 years but the course of the
disease was milder than the infantile nephropathic form. This suggests that
the missense mutations found in these individuals allow production of
functional protein and may also indicate regions of cystinosin which are
not functionally important.
ARTICLES
Severity of phenotype in cystinosis varies with mutations in the CTNS gene: predicted effect on the model of cystinosin
Nephrourology Unit, Institute of Child Health, University College London Medical School, 30 Guilford Street, London WC1N 1EH, UK,
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