Analysis of the CTNS gene in patients of German and Swiss origin with nephropathic cystinosis

Abstract

The autosomal recessive lysosomal storage disorder, nephropathic cystinosis is characterized by impaired transport of free cystine out of lysosomes. The gene responsible for cystinosis, CTNS, consists of 12 exons and encodes a 55 kDa putative lysosomal membrane protein, called cystinosin. Up to now more than 55 different CTNS mutations have been described in cystinosis. We have analyzed the mutation pattern in a population of 40 cystinosis patients from 35 families of German and Swiss origin. CTNS mutations in 68 out of 70 alleles were identified. The common 57-kb deletion accounted for 65% of the alleles. In five patients we found a known GACT deletion at position 18-21. In two patients we identified a nucleotide substitution at codon 339 and one patient showed a CG insertion at position 697-698. In five patients we observed a G insertion at position 926-927. Moreover, five novel mutations including two deletions involving exon 3 (61-61+2delGGT) and exon 6 (280delG), two insertions in exon 6 (292-293insA) and exon 7 (684insCACTT) and one nucleotide substitution in exon 11 (923G>T) have been identified. These data provide a basis for routine molecular diagnosis of cystinosis in the central European population, especially in cystinosis patients of German and Swiss origin.

Mutational spectrum of the CTNS gene in Italy

“…To explain the high proportion of deletions found in his population, Shotelersuk suggested that the short arm of chromosome 17 might be susceptible to deletions. 7,23 Our data, as well as the French -Canadians results, in which a much lower proportion of deletions was detected, contrast with this hypothesis, and support the hypothesis that this mutation originated from Northern Europe; 13,17 indeed, the 57-kb mutation is not widespread in North Italy, while the 13-kb deletion is present mainly in South Italy.…”

Mutational Spectrum of the CTNS Gene in Egyptian Patients with Nephropathic Cystinosis

“…Likewise, the small deletion c.809_811del; p. S270del was tested functionally and resulted in almost complete loss of function (Kalatzis et al 2004). The most widely distributed among the six previously reported mutations in Egyptian patients was c.1015G>A; p. G339R, as it was reported in Turkey (Topaloglu et al 2012), Italy (Mason et al 2003), Germany (Kiehntopf et al 2002), France (Attard et al 1999), Spain (Macías-Vidal et al 2009), the USA (Shotelersuk et al 1998), and Canada (Rupar et al 2001), followed by c.922G>A; p.G308R reported in Saudi Arabia (Aldahmesh et al 2009), Italy (Mason et al 2003), France (Attard et al 1999), Spain (Macías-Vidal et al 2009), and the USA (Shotelersuk et al 1998). The mutation c.809_811del; p.S270del was also relatively widespread, as it was reported in France (Attard et al 1999) and India (Tang et al 2009) (Fig.…”

A homemade MLPA assay detects known CTNS mutations and identifies a novel deletion in a previously unresolved cystinosis family

“…In contrast to other cases (Kiehntopf et al, 2002;our unpublished data), no mutation could be identified by applying a breakpoint PCR for the known 57 kb deletion (Anikster et al, 1999a) and by repeatedly sequencing the coding exons 3 to 12. The index patient had been born to parents of Turkish origin; no consanguinity was reported at the time of diagnosis.…”

“…We next analyzed selected DNA samples previously shown to carry deletions in the CTNS gene (Kiehntopf et al, 2002;our unpublished data). Control probes as well as probes for exons known to not be affected showed RS-values of around 1.0 again (range 0.77 to 1.14).…”

“…A large deletion of 57 kb including the first 10 exons (Town et al, 1998) represents the most frequent single mutation identified thus far. It accounts for up to 65% of cystinosis alleles in patients of Swiss and German origin (Kiehntopf et al, 2002), and likely represents a founder mutation (Anikster et al, 1999a). In addition, causative nucleotide substitutions in the promotor and in deep intronic sequence as well as other large deletions and one large duplication have been identified (Town et al, 1998;Anikster et al, 1999b;Phornphutkul et al, 2001;Taranta et al, 2010;Topaloglu et al, 2012).…”