Article

Identification of novel WFS1 mutations in Italian children with Wolfram syndrome

Molecular Medicine and Diabetology, IRCCS-Bambino Gesù, Rome.
Human Mutation (Impact Factor: 5.05). 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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    • "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 http://www.khri.med.umich.edu/research/lesperance_lab/wfs_delete.php). 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 · 2.05 Impact Factor
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    • "As expected, all seven homozygous patients for this mutation (Cases 4–9 and 11) shared common clinical features, including the occurrence of the four cardinal symptoms of the syndrome (DI-DM-OA-D) in the first two decades of the patients' life, as well as urinary tract dilatation. Interestingly, a previous study detected a different 16-bp deletion starting at nucleotide 1519 in two young Italian WS patients, who carried the mutation in both alleles [Tessa et al., 2001]. This out-of-frame deletion was similar to the one found in our series of patients, in that both of them were predicted to create a premature stop codon, leading to the loss of six transmembrane domains and the carboxy terminal end of wolframin. "
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    ABSTRACT: Wolfram syndrome (WS) is a recessively inherited mendelian form of diabetes and neurodegeneration also known by the acronym DIDMOAD from the major clinical features, including diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. Affected individuals may also show renal tract abnormalities as well as multiple neurological and psychiatric symptoms. The causative gene for WS (WFS1) encoding wolframin maps to chromosome 4p16.1 and consists of eight exons, spanning 33.44 Kb of genomic DNA. In this study we report on the mutational analysis of the WFS1 coding region in 19 Italian WS patients and 25 relatives, using a DHPLC-based protocol. A total of 19 different mutations in WFS1 were found in 18 of 19 patients (95%). All these mutations, except one, are novel, preferentially located in WFS1 exon 8, and include deletions, insertions, duplications, and nonsense and missense changes. In particular, a 16 base-pair deletion in WFS1 codon 454 was detected in five different unrelated nuclear families, being the most prevalent alteration in this Italian group. Nine neutral changes and polymorphisms were also identified. Overall, this study represents the molecular characterization of the largest cohort of Italian WS patients and carriers studied so far, and increases the number of identified WFS1 allelic variants worldwide.
    Human Mutation 06/2003; 21(6):622-9. DOI:10.1002/humu.10215 · 5.05 Impact Factor
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    ABSTRACT: Identification of environmental information critical for survival and procreation is crucial for forming appropriate behavioral responses. An important psychological aspect of this process is emotion perception. Impaired or distorted perception of emotions is characteristic of almost all psychiatric disorders and is accompanied by reduced coping with everyday life. In the present study we screened for genes involved in the regulation of emotional behavior and observed that cat odor-induced fear response in rats coincides with the induction of Wfs1 mRNA in the amygdaloid area. Additionally, a number genes involved directly or indirectly in the synthesis of neurotransmitters (e.g. carboxypeptidase E, tyrosine 3-monooxygenase/ tryptophan 5-mono-oxygenase activation protein) and in signal transduction (Rho GTPase, neurochondrin, Ca/calmodulin-dependent protein kinase) were activated. Next, we determined the expression pattern of Wfs1 protein in the central nervous system of the mouse. Wfs1 expression is enriched in brain structures related to (1) behavioral adaptation – amygdaloid complex, bed nucleus of stria terminalis, the core and shell fields of nucleus accumbens, the prefrontal cortex and the CA1 field of hippocampus; (2) hearing – inferior colliculus, lateral lemniscus, primary auditory cortex; (3) the regulation of endocrine function – supraoptic and paraventricular hypothalamic nuclei, the arcuate nucleus; (4) cortical regions related to hippocampal function – perirhinal, postrhinal and entorhinal cortices, parasubiculum. Two functional-anatomical macrosystems – the central extended amygdala (central nucleus of amygdala, interstitial nucleus of posterior limb of anterior commissure and lateral bed nucleus of stria terminalis) and ventral striatum (nucleus accumbens and olfactory tubercle) form a continuous field of Wfs1-enriched neurons spanning the basal forebrain. Finally, we created a Wfs1-deficient mouse strain in order to uncover the behavioral effects of Wfs1. Wfs1-deficiency resulted in higher anxiety response in stressful situations as indicated by increased eating latency in hyponeophagia test, lower exploration in brightly lit motility box, anxiety-like behavior in dark-light box test after short-term social isolation, a nearly three-fold higher plasma corticosterone concentration after handling and injection stress, and higher sensitivity to a moderate dose of diazepam in the plus-maze test. Additionally, a subset of Wfs1-deficient mice produced spontaneous audible vocalizations which increased in loudness under stressful conditions and were suppressed by the administration of diazepam. Wfs1-deficient mice display altered pharmacological responsiveness of the mesolimbic dopamine pathway as evidenced by differential sensitivity to amphetamine and apomorphine. The stimulatory effect of amphetamine at intermediate and high doses was significantly weaker in Wfs1-deficient mice, probably indicating lower presynaptic release potential for dopamine in the mesolimbic pathway. Conversely postsynaptic dopamine receptor agonist apomorphine induced significantly higher locomotor activation in Wfs1-deficient mice reflecting most likely postsynaptic upregulation of dopamine receptors in the mesolimbic area. Conclusions: (1) Wfs1 expression pattern in the mouse brain correlates with hearing loss, diabetes insipidus and psychiatric symptoms found in Wolfram Syndrome patients. (2) In mice, Wfs1-deficiency results in increased anxiety-like behavior which is apparent in stressful situations. Nii inimesel kui paljudel teistel liikidel on emotsioonide tajumine oluliseks kohanemiskäitumise osaks. Emotsioonid annavad meist väljaspool toimuvatele sündmustele hinnangu, mille tulemusena tekib organismi valmisolek nendele reageerimiseks. Emotsionaalse käitumise geneetiliste tegurite uurimine on viimastel aastakümnetel muutunud suureks uurimisvaldkonnaks, mis peamiselt loomkatsete abil püüab tuvastada geene, mida saaks rakendada psühhiaatriliste häirete ravimsihtmärkideks. Osaliselt tänu käesoleva töö tulemustele on üheks uueks kandidaadiks Wfs1 (Wolfram syndrome locus 1) geen, mis on oma nime saanud seoses haruldase päriliku haigusega, mis kannab nime Wolfram'i sündroom. Varasemad uuringud on näidanud, et veerandil Wolfram'i sündroomiga patsientidest esineb raskeid psühhiaatrilisi sümptomeid. Käesolevas töös leiti, et Wfs1 geeni ekspressioon roti mandelkehas suurenes pärast kassi lõhna poolt tekitatud hirmureaktsiooni. Lisaks oli suurenenud mitmete närviülekandega ja rakusisese signaaliülekandega seotud geenide ekspressioon (kaarboksüpeptidaas E, türosiin 3-monooksügenaasi aktiveeriv valk, Rho GTPaas, Ca-kalmoduliin-sõltuv kinaas jt.). Seejärel tuvastati Wfs1 valgu levik hiire kesknärvisüsteemis ja leiti, et Wfs1 ekspressioon on eriti tugev (1) kohanemiskäitumise regulatsiooniga seotud struktuurides - mandelkeha kompleks, sängituum, naalduv tuum, prefrontaalkoor, hipokampuse CA1 piirkond; (2) kuulmisega seotud struktuurides – alumine nelikküngastik, lateraalne lemniskus, primaarne kuulmiskoor; (3) endokriinfunktsiooni regulatsiooniga seotud struktuurides – supraoptiline tuum, paraventrikulaartuum, nucleus arcuatus; (4) hipokampuse talitlusega seotud ajukoore osad – peririnaalkoor, postrinaalkoor, entorinaalkoor, parasubiikulum. Seejärel loodi Wfs1 geeni puudulikkusega hiir, et uurida Wfs1 valgu puudumise mõju käitumisele. Wfs1-puudulikkus põhjustas hiirtel suurenenud ärevuse stressitekitavas keskkonnas, mis väljendus pikenenud söömislatentsina hüponeofaagia testis, väiksema uudistamisaktiivsusena intensiivse valgusega liikumisaktiivsuse testis, ärevuslaadse käitumisena hele-tume puuris pärast lühiajalist sotsiaalset isolatsiooni, kolm korda suurenenud kortikosterooni vastusena pärast süstimist ja käsitsemist, ja diasepaami suurenenud anksiolüütilise toimena plusspuuris. Kuni neljandik Wfs1-puudulikkusega hiirtest tõi kuuldavale spontaanseid häälitsusi, mis vaibusid pärast diasepaami manustamist. Wfs1-puudulikel hiirtel oli muutunud mesolimbilise dopamiinisüsteemi tundlikkus. Amfetamiini motoorikat stimuleeriv toime oli keskmises ja suures doosis nõrgem kui metsiktüüpi hiirtel. Sellele vastupidiselt põhjustas apomorfiini manustamine oluliselt suuremat motoorika aktivatsiooni kui metsiktüüpi hiirtel. Järeldused: (1) Wfs1 valgu ekspressioonimuster hiire ajus korreleerub kuulmiskahjustuse, magediabeedi ja psühiaatriliste sümptomite esinemisega Wolframi sündroomiga patsientidel (2) Wfs1 geeni puudulikkus põhjustab hiirtes ärevuselaadse seisundi, mis on eriti ilmne stressitekitavates olukordades.
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