Identification of novel WFS1 mutations in Italian children with Wolfram syndrome

Molecular Medicine and Diabetology, IRCCS-Bambino Gesù, Rome.
Human Mutation (Impact Factor: 5.14). 04/2001; 17(4):348-9. DOI: 10.1002/humu.32
Source: PubMed

ABSTRACT Six unrelated Italian children with Wolfram syndrome (WS) were analyzed for mutations in the WFS1. Four novel mutations (1387delCTCT, S443I, 1519del16, and IVS6+16g->a) were identified. In addition, we found two new, probably neutral changes (A684V and R708C). Other previously described variants were a heterozygous I333V in three alleles and the H611R in two. The 1519del16 mutation was carried by two patients whereas the CTCT deletion occurred in three subjects from two apparently unrelated families with WS. The current study expands the spectrum of mutations in WFS1 and represents the first molecular characterization of Italian WS patients.

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Available from: Renata Lorini, Sep 08, 2014
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    • "Mutational screening, conducted in our Laboratory, revealed a total of 14 distinct variants (7 missense, 2 nonsense, 5 frameshift) all located in exon 8 except the c. 409_424dup16 in exon 4. Twelve were already described (c.1628T>G, c.2104 G>A, c.1060_1062delTTC, c.1620delGTG, c.2020 G>A, c.1885C>T, c.1230_1233delCTCT, c.1582 T>G, c.2106_2113del8n, c.2051C>T, c.1456 C>T, c.409_424dup16) [15], [16], [17], [15], [18], [19], [20], [21], [21]–[22,23,15,24] and two: the c.2663 C>A, p. S888X; and the c.1381 A>C, p. T461P were novel (Table 2). In order to establish the correct allelic segregation, DNA of parents were sequenced in all cases except in parents of proband 7, whose DNA sample was not available when molecular investigation was performed. "
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    ABSTRACT: Wolfram Syndrome (WS) is an autosomal recessive neurodegenerative disorder characterized by Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness identified by the acronym "DIDMOAD". The WS gene, WFS1, encodes a transmembrane protein called Wolframin, which recent evidence suggests may serve as a novel endoplasmic reticulum calcium channel in pancreatic β-cells and neurons. WS is a rare disease, with an estimated prevalence of 1/550.000 children, with a carrier frequency of 1/354. The aim of our study was to determine the genotype of WS patients in order to establish a genotype/phenotype correlation. We clinically evaluated 9 young patients from 9 unrelated families (6 males, 3 females). Basic criteria for WS clinical diagnosis were coexistence of insulin-treated diabetes mellitus and optic atrophy occurring before 15 years of age. Genetic analysis for WFS1 was performed by direct sequencing. Molecular sequencing revealed 5 heterozygous compound and 3 homozygous mutations. All of them were located in exon 8, except one in exon 4. In one proband only an heterozygous mutation (A684V) was found. Two new variants c.2663 C>A and c.1381 A>C were detected. Our study increases the spectrum of WFS1 mutations with two novel variants. The male patient carrying the compound mutation [c.1060_1062delTTC]+[c.2663 C>A] showed the most severe phenotype: diabetes mellitus, optic atrophy (visual acuity 5/10), deafness with deep auditory bilaterally 8000 Hz, diabetes insipidus associated to reduced volume of posterior pituitary and pons. He died in bed at the age of 13 years. The other patient carrying the compound mutation [c.409_424dup16]+[c.1381 A>C] showed a less severe phenotype (DM, OA).
    PLoS ONE 01/2012; 7(1):e29150. DOI:10.1371/journal.pone.0029150 · 3.23 Impact Factor
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    • "Prior to our study, the p.A684V mutation had not been reported in association with an isolated OA and hearing loss phenotype. However, this mutation had been identified in a patient from Italy with Wolfram syndrome [Tessa et al., 2001] (Family 3 at the WFS1 Gene Mutation and Polymorphism Database at The Italian patient had diabetes mellitus, optic atrophy, hearing loss, diabetes insipidus, ataxic gait and psychiatric abnormalities. "
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    ABSTRACT: Optic atrophy (OA) and sensorineural hearing loss (SNHL) are key abnormalities in several syndromes, including the recessively inherited Wolfram syndrome, caused by mutations in WFS1. In contrast, the association of autosomal dominant OA and SNHL without other phenotypic abnormalities is rare, and almost exclusively attributed to mutations in the Optic Atrophy-1 gene (OPA1), most commonly the p.R445H mutation. We present eight probands and their families from the US, Sweden, and UK with OA and SNHL, whom we analyzed for mutations in OPA1 and WFS1. Among these families, we found three heterozygous missense mutations in WFS1 segregating with OA and SNHL: p.A684V (six families), and two novel mutations, p.G780S and p.D797Y, all involving evolutionarily conserved amino acids and absent from 298 control chromosomes. Importantly, none of these families harbored the OPA1 p.R445H mutation. No mitochondrial DNA deletions were detected in muscle from one p.A684V patient analyzed. Finally, wolframin p.A684V mutant ectopically expressed in HEK cells showed reduced protein levels compared to wild-type wolframin, strongly indicating that the mutation is disease-causing. Our data support OA and SNHL as a phenotype caused by dominant mutations in WFS1 in these additional eight families. Importantly, our data provide the first evidence that a single, recurrent mutation in WFS1, p.A684V, may be a common cause of ADOA and SNHL, similar to the role played by the p.R445H mutation in OPA1. Our findings suggest that patients who are heterozygous for WFS1 missense mutations should be carefully clinically examined for OA and other manifestations of Wolfram syndrome.
    American Journal of Medical Genetics Part A 06/2011; 155A(6):1298-313. DOI:10.1002/ajmg.a.33970 · 2.16 Impact Factor
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    • "Subsequent functional studies demonstrated that WFS1 protein is important in the regulation of intracellular Ca 2 homeostasis and its expression is induced under conditions of troubled homeostasis, including ER stress (Osman et al., 2003; Yamaguchi et al., 2004; Ueda et al., 2005; Takei et al., 2006). In addition, mutation screening analyses in Wolfram syndrome patients showed more than 50 distinct mutations of the WFS1 gene, including stop, frameshift, deletion, and missense mutations (Inoue et al., 1998; Strom et al., 1998; Hardy et al., 1999; Gómez-Zaera et al., 2001; Khanim et al., 2001; Tessa et al., 2001). Thus, lossof-function mutations in the WFS1 gene have been linked to Wolfram syndrome. "
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    ABSTRACT: Confocal laser scanning microscope image of double immunostaining for Wfs1 protein (green) and for glial fibrillary acidic protein (GFAP; an astrocyte marker; red) in the normal mouse retina and optic nerve. Cell nuclei are labeled in blue. The Wfs1 protein, also called wolframin, is the Wolfram syndrome 1 (Wfs1) gene product. Wfs1 is the disease gene for Wolfram syndrome, a neurodegenerative disorder defined by insulin-dependent diabetes mellitus and progressive optic atrophy. This image shows that Wfs1 immunoreactivity is observed in the GFAP-rich part of the optic nerve immediately behind the eye (central part of the image), and in most of the retinal layers (lower part of the image). J. Comp. Neurol. 510:1-23, 2008. (c) 2008 Wiley-Liss, Inc.
    The Journal of Comparative Neurology 09/2008; 510(1):SPC1. DOI:10.1002/cne.21797 · 3.23 Impact Factor
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