Optic atrophy in Wolfram syndrome

Mtanda, A. T.; Cruysberg, J.R.M.; Pinckers, A.

doi:10.3109/13816818609004133

Cited by 20 publications

(23 citation statements)

References 15 publications

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“…Our Cisd2 gene knockout mouse work provides strong evidence supporting the hypothesis that WFS is a mitochondria-mediated disorder; thus, specifically, WFS2, which is caused by a CISD2 mutation, is a mitochondria-mediated disorder. Previous clinical studies in WFS patients suggested that optic atrophy probably represents a degeneration of the optic nerve (Mtanda et al 1986;. Indeed, our mouse work has revealed that progressive degeneration of the optic nerve is one of the earliest phenotypic features detected at 2-3 wk of age, which is before weaning; this phenotype exacerbates with age in the Cisd2 À/À offspring ( Fig.…”

Section: Wfs2 Is a Mitochondria-mediated Disordermentioning

confidence: 73%

Cisd2 deficiency drives premature aging and causes mitochondria-mediated defects in mice

Chen¹,

Kao²,

Chen³

et al. 2009

Genes Dev.

248

260

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CISD2, the causative gene for Wolfram syndrome 2 (WFS2), is a previously uncharacterized novel gene. Significantly, the CISD2 gene is located on human chromosome 4q, where a genetic component for longevity maps. Here we show for the first time that CISD2 is involved in mammalian life-span control. Cisd2 deficiency in mice causes mitochondrial breakdown and dysfunction accompanied by autophagic cell death, and these events precede the two earliest manifestations of nerve and muscle degeneration; together, they lead to a panel of phenotypic features suggestive of premature aging. Our study also reveals that Cisd2 is primarily localized in the mitochondria and that mitochondrial degeneration appears to have a direct phenotypic consequence that triggers the accelerated aging process in Cisd2 knockout mice; furthermore, mitochondrial degeneration exacerbates with age, and the autophagy increases in parallel to the development of the premature aging phenotype. Additionally, our Cisd2 knockout mouse work provides strong evidence supporting an earlier clinical hypothesis that WFS is in part a mitochondria-mediated disorder; specifically, we propose that mutation of CISD2 causes the mitochondriamediated disorder WFS2 in humans. Thus, this mutant mouse provides an animal model for mechanistic investigation of Cisd2 protein function and help with a pathophysiological understanding of WFS2.[Keywords: Cisd2; Wolfram syndrome 2; autophagy; knockout mice; mitochondria; premature aging] Supplemental material is available at http://www.genesdev.org.

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Section: Wfs2 Is a Mitochondria-mediated Disordermentioning

confidence: 73%

Cisd2 deficiency drives premature aging and causes mitochondria-mediated defects in mice

Chen¹,

Kao²,

Chen³

et al. 2009

Genes Dev.

248

260

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“…The age of onset and clinical features of the Wolfram syndrome patients are shown in table 1; some of these have been described previously [van den Ouweland, 2003;Mtanda et al, 1986]. Figure 2 shows the audiometric data (single and serial observations) obtained for all patients with Wolfram syndrome and their non-affected heterozygous relatives (carriers) with one WFS1 mutation, arranged by family.…”

Section: Resultsmentioning

confidence: 99%

Sex-Related Hearing Impairment in Wolfram Syndrome Patients Identified by Inactivating <i>WFS1</i> Mutations

et al. 2003

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This study examined the audiovestibular profile of 11 Wolfram syndrome patients (4 males, 7 females) from 7 families, with identified WFS1 mutations, and the audiometric profile of 17 related heterozygous carriers of WFS1 mutations. Patients with Wolfram syndrome showed a downsloping audiogram and progressive hearing impairment. None of the carriers had sensorineural hearing loss. Two patients with missense (non-inactivating) mutations in WFS1 had normal hearing and mild symptoms of Wolfram syndrome and were excluded from the analyses. Of the identified patients with inactivating WFS1 mutations, 5 female patients were significantly more hearing impaired than four male patients (p < 0.05). Female patients showed hearing impairment progressing by 1.5–2.0 dB HL per year for the low frequencies and 4.0–4.5 dB HL per year for the mid and high frequencies. The age of onset (90% phoneme recognition score) was 21 years and the onset level 78 dB HL. The deterioration rate was 4.0% per year and the deterioration gradient 1.4% per dB HL. One of the 6 examined patients had vestibular areflexia.

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“…Instead, Wfs1 is probably distributed as an ER membrane protein in the inner segments and cell bodies of photoreceptors (Takeda et al, 2001;Hofmann et al, 2003), and is considered responsible for the maintenance of phototransduction. In addition, slight photoreceptor dysfunction is suspected in Wolfram syndrome patients (Yamamoto et al, 2006), since the subjective dark adaptation curve in Wolfram syndrome patients shows a diminution of both cone and rod adaptation (Mtanda et al, 1986).…”

Section: The Journal Of Comparative Neurologymentioning

confidence: 99%

“…The ophthalmologic signs are a progressive decrease in visual acuity, constriction of the peripheral visual field with or without central scotoma, color vision disturbance, and bilateral optic disc atrophy. Diabetic retinopathy is a rare complication (Mtanda et al, 1986;Seynaeve et al, 1994;Barrett et al, 1997). Although a profound reduction in visual function is observed in Wolfram syndrome patients, the electroretinogram (ERG) tests indicate normal or only slightly reduced responses (Niemeyer and Marquardt, 1972;Mtanda et al, 1986;Seynaeve et al, 1994;Barrett et al, 1997).…”

mentioning

confidence: 99%

“…Diabetic retinopathy is a rare complication (Mtanda et al, 1986;Seynaeve et al, 1994;Barrett et al, 1997). Although a profound reduction in visual function is observed in Wolfram syndrome patients, the electroretinogram (ERG) tests indicate normal or only slightly reduced responses (Niemeyer and Marquardt, 1972;Mtanda et al, 1986;Seynaeve et al, 1994;Barrett et al, 1997). These findings suggest that the site of pathology for optic atrophy lies not in the retina, but in the visual pathway proximal (posterior) to the eye including the optic nerve (Barrett et al, 1997).…”

mentioning

confidence: 99%

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Wolfram syndrome 1 (Wfs1) gene expression in the normal mouse visual system

Kawano¹,

Tanizawa²,

Shinoda³

2008

J of Comparative Neurology

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Wolfram syndrome (OMIM 222300) is a neurodegenerative disorder defined by insulin-dependent diabetes mellitus and progressive optic atrophy. This syndrome has been attributed to mutations in the WFS1 gene, which codes for a putative multi-spanning membrane glycoprotein of the endoplasmic reticulum. The function of WFS1 (wolframin), the distribution of this protein in the mammalian visual system, and the pathogenesis of optic atrophy in Wolfram syndrome are unclear. In this study we made a detailed analysis of the distribution of Wfs1 mRNA and protein in the normal mouse visual system by using in situ hybridization and immunohistochemistry. The mRNA and protein were observed in the retina, optic nerve, and brain. In the retina, Wfs1 expression was strong in amacrine and Müller cells, and moderate in photoreceptors and horizontal cells. In addition, it was detectable in bipolar and retinal ganglion cells. Interestingly, moderate Wfs1 expression was seen in the optic nerve, particularly in astrocytes, while little Wfs1 was expressed in the optic chiasm or optic tract. In the brain, moderate Wfs1 expression was observed in the zonal, superficial gray, and intermediate gray layers of the superior colliculus, in the dorsomedial part of the suprachiasmatic nucleus, and in layer II of the primary and secondary visual cortices. Thus, Wfs1 mRNA and protein were widely distributed in the normal mouse visual system. This evidence may provide clues as to the physiological role of Wfs1 protein in the biology of vision, and help to explain the selective vulnerability of the optic nerve to WFS1 loss-of-function.

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Optic atrophy in Wolfram syndrome

Cited by 20 publications

References 15 publications

Cisd2 deficiency drives premature aging and causes mitochondria-mediated defects in mice

Cisd2 deficiency drives premature aging and causes mitochondria-mediated defects in mice

Sex-Related Hearing Impairment in Wolfram Syndrome Patients Identified by Inactivating <i>WFS1</i> Mutations

Wolfram syndrome 1 (Wfs1) gene expression in the normal mouse visual system

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