CTNS Mutations in an American-Based Population of Cystinosis Patients

Abstract

Nephropathic cystinosis is an autosomal recessive lysosomal storage disease characterized by renal failure at 10 years of age and other systemic complications. The gene for cystinosis, CTNS, has 12 exons. Its 2.6-kb mRNA codes for a 367-amino-acid putative cystine transporter with seven transmembrane domains. Previously reported mutations include a 65-kb "European" deletion involving marker D17S829 and 11 small mutations. Mutation analysis of 108 American-based nephropathic cystinosis patients revealed that 48 patients (44%) were homozygous for the 65-kb deletion, 2 had a smaller major deletion, 11 were homozygous and 3 were heterozygous for 753G-->A (W138X), and 24 had 21 other mutations. In 20 patients (19%), no mutations were found. Of 82 alleles bearing the 65-kb deletion, 38 derived from Germany, 28 from the British Isles, and 4 from Iceland. Eighteen new mutations were identified, including the first reported missense mutations, two in-frame deletions, and mutations in patients of African American, Mexican, and Indian ancestry. CTNS mutations are spread throughout the leader sequence, transmembrane, and nontransmembrane regions. According to a cystinosis clinical severity score, homozygotes for the 65-kb deletion and for W138X have average disease, whereas mutations involving the first amino acids prior to transmembrane domains are associated with mild disease. By northern blot analysis, CTNS was not expressed in patients homozygous for the 65-kb deletion but was expressed in all 15 other patients tested. These data demonstrate the origins of CTNS mutations in America and provide a basis for possible molecular diagnosis in this population.

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

“…Ten out of 15 patients had homozygous mutations. Six previously reported CTNS mutations were detected in our study: c.829dup; p.T277NfsX19 (Besouw et al 2012), c.922G>A; G308R (Shotelersuk et al 1998), 809_811delCCT; p.S270del (Attard et al 1999), c.15G>A; p.W5X , c.681G>A; E227E (Aldahmesh et al 2009), and c.1015G>A; p.G339R (Shotelersuk et al 1998). All these mutations were previously associated with infantile nephropathic cystinosis in various populations.…”

“…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.…”

The impact of chromosomal microarray on clinical management: a retrospective analysis

“…Cystinosis (OMIM 219800) was highly suspected, but because biochemical studies returned equivocal results and insurance issues impeded approval for gene-specific testing, CMA was subsequently ordered to test for the most common mutation underlying this disorder, a 57 kb partial deletion of CTNS. 25 The array revealed a homozygous deletion of this segment, thereby confirming the diagnosis of cystinosis. This allowed the patient to immediately begin treatment with cysteamine, a compound that helps to preserve renal function and improve growth in patients with cystinosis.…”

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

“…CTNS comprises twelve exons spanning 24 kb of genomic DNA and encodes for a 367 amino acid protein which is predicted to be an integral lysosomal membrane protein with seven transmembrane domains. In nephropathic cystinosis a number of mutations in CTNS have been identified; Shotelersuk et al, 1998;Town et al, 1998). The most common mutation causing the infantile nephropathic form of cystinosis is a 57-kb deletion involving most of the CTNS gene (Touchman et al, 2000;Town et al, 1998).…”

“…In addition to this most frequent alteration, smaller deletions, missense mutations, and frameshifts have been described in European and Americanbased populations of cystinosis patients leading to downstream stop codons or abolition of splice sites. Attard et al, 1999;Heil et al, 2001;Kleta et al, 2001;McGowan-Jordan et al, 1999;Rupar et al, 2001;Shotelersuk et al, 1998;Town et al, 1998).…”