title: Identification of 14 novel CTNS mutations and characterization of seven splice site mutations associated with cystinosis.
abstract: Cystinosis is an autosomal recessive disorder characterized by intra-lysosomal accumulation of cystine. Three disease forms exist, infantile, juvenile, and ocular nonnephropathic cystinosis, delineated on the basis of severity of symptoms and age of onset. Mutations in the causative gene, CTNS, which encodes cystinosin, the seven transmembrane domain lysosomal cystine transporter, have been identified in all forms confirming their allelic status. By screening for mutations in the CTNS exons and promotor region, we report 14 novel mutations associated with cystinosis: 11 underlying infantile cystinosis, two juvenile cystinosis, and one associated with an atypical form of the disease. These mutations, all situated in the exons or immediately flanking intronic sequences, comprise in-frame insertions and deletions, as well as missense, nonsense, and putative splice-site mutations. Furthermore, we confirmed the putative splice-site mutations we have reported to date (five novel and two previously reported) by isolation of RNA from the affected carriers and characterization of the resultant transcripts using RT-PCR. Since the cloning of CTNS, we have screened for mutations in 108 affected individuals, which has resulted in a high mutation detection rate of 95.8%. Interestingly, the few undetectable mono- or bi-allelic mutations segregated mostly in the noninfantile forms, suggesting that these individuals carry mutations either in the introns or in unidentified regulatory sequences.
authors.affiliation: Inserm U423, Hôpital Necker-Enfants Malades, Université René Descartes, Paris, France.
authors.forename: Vasiliki
authors.initials: V
authors.lastname: Kalatzis
authors.forename: Lola
authors.initials: L
authors.lastname: Cohen-Solal
authors.forename: Béatrice
authors.initials: B
authors.lastname: Cordier
authors.forename: Yaacov
authors.initials: Y
authors.lastname: Frishberg
authors.forename: Markus
authors.initials: M
authors.lastname: Kemper
authors.forename: E Matti
authors.initials: EM
authors.lastname: Nuutinen
authors.forename: Eric
authors.initials: E
authors.lastname: Legrand
authors.forename: Pierre
authors.initials: P
authors.lastname: Cochat
authors.forename: Corinne
authors.initials: C
authors.lastname: Antignac
mesh_terms: D000293:Adolescent; D000328:Adult; D017398:Alternative Splicing / Q000235:genetics*; D026921:Amino Acid Transport Systems, Neutral; D002648:Child; D003554:Cystinosis / Q000235:genetics* / Q000473:pathology; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D005796:Genes / Q000235:genetics; D006023:Glycoproteins; D006579:Heterozygote; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D026901:Membrane Transport Proteins; D012313:RNA / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D026921:Amino Acid Transport Systems, Neutral; C111445:CTNS protein, human; D006023:Glycoproteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D012313:RNA; D004247:DNA