Identification of 14 novelCTNS mutations and characterization of seven splice site mutations associated with cystinosis

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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. Hum Mutat 20:439–446, 2002.