Identification of p.A684V Missense Mutation in the WFS1 Gene as a Frequent Cause of Autosomal Dominant Optic Atrophy and Hearing Impairment

Wilhelm Johannsen Centre for Functional Genome Research, Department of Cellular and Molecular Medicine, The Panum Institute, University of Copenhagen, Denmark.
American Journal of Medical Genetics Part A (Impact Factor: 2.16). 06/2011; 155A(6):1298-313. DOI: 10.1002/ajmg.a.33970
Source: PubMed


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.

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Available from: Toril Fagerheim, Jul 04, 2014
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    • "Three other loci have been associated with autosomal DOA and designated as OPA4 (19), OPA5 (20), and OPA8 (21). Furthermore, heterozygous mutations in the OPA3 gene have been associated with DOA and cataract (22), as well as heterozygous mutations in the WSF1 gene have been reported in association with DOA and hearing loss (23). Both OPA3 and WSF1 genes are mostly associated with recessive mutations leading to Costeff (24) and Wolfram syndromes, respectively. "
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    ABSTRACT: Hereditary optic neuropathies are diseases affecting the optic nerve. The most common are mitochondrial hereditary optic neuropathies, i.e., the maternally inherited Leber's hereditary optic neuropathy (LHON) and dominant optic atrophy (DOA). They both share a mitochondrial pathogenesis that leads to the selective loss of retinal ganglion cells and axons, in particular of the papillo-macular bundle. Typically, LHON is characterized by an acute/subacute loss of central vision associated with impairment of color vision and swelling of retinal nerve fibers followed by optic atrophy. DOA, instead, is characterized by a childhood-onset and slowly progressive loss of central vision, worsening over the years, leading to optic atrophy. The diagnostic workup includes neuro-ophthalmologic evaluation and genetic testing of the three most common mitochondrial DNA mutations affecting complex I (11778/ND4, 3460/ND1, and 14484/ND6) for LHON and sequencing of the nuclear gene OPA1 for DOA. Therapeutic strategies are still limited including agents that bypass the complex I defect and exert an antioxidant effect (idebenone). Further strategies are aimed at stimulating compensatory mitochondrial biogenesis. Gene therapy is also a promising avenue that still needs to be validated.
    Full-text · Article · Jul 2014 · Frontiers in Neurology
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    • "was not excluded in this case due to ethical reasons. Previously, heterozygous WFS1 variants have been associated with early-onset profound HI in six families (Hansen et al, 2005; Hogewind et al, 2010; Rendtorff et al, 2011; Eiberg et al, 2013), but only p.His313Tyr in two families has been verifi ed to be a de novo mutation (Hansen et al, 2005). In the six families, there were 11 subjects with the WFS1 mutation and with HI, and all of them developed optic atrophy at a median age of 11 years (range, 6 – 41 years), whereas our proband at age 19 years does not have visual problems. "
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    ABSTRACT: Abstract Objective: Mutations in the WFS1 gene can cause Wolfram syndrome or nonsyndromic hearing impairment (HI). The objective of this study was to ascertain the presence of mutations in WFS1 among children with HI from unknown causes. Design: We screened 105 Finnish children with HI for mutations in exon 8 in WFS1. Study sample: Children were born in a defined area in Northern Finland and they had sensorineural, mild to profound, syndromic, or nonsyndromic HI. They were negative for GJB2 mutations and for the m.1555A> G and m.3243A> G mutations in mitochondrial DNA. Results: We found three rare variants and the novel p.Gly831Ser variant in WFS1. Segregation analysis suggested that the novel variant had arisen de novo. The p.Gly831Ser variant may be a new member to the group of heterozygous WFS1 mutations that lead to HI, while the pathogenicity of the rare variant p.Gly674Arg remained unclear. The other two rare variants, p.Glu385Lys and p.Glu776Val, did not segregate with HI in the families. Conclusions: WFS1 gene mutations are a rare cause of HI among Finnish children with HI.
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    • "The genetic basis of WS was clarified by identifying a locus for WS on chromosome 4p16.1 in 1994 (Polymeropoulos et al., 1994) and subsequently the causative mutations in a gene (WFS1) encoding for an endoplasmic reticulum (ER) transmembrane protein named Wolframin (Inoue et al., 1998). WFS1 mutations may behave as a dominant (Eiberg et al., 2006) or a recessive trait (Rendtorff et al., 2011; Tranebjaerg et al., 2009). The exact function of Wolframin is still under investigation, but its role in the ER-stress response (Fonseca et al., 2005; Yamada et al., 2006), including Na + /K + ATPase dysfunction mediated by the wolframin-interacting protein β1 subunit (Zatyka et al., 2008), as well as defective calcium handling (Osman et al., 2003; Takei et al., 2006), have all been documented. "
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    ABSTRACT: Mitochondrial dysfunction in Wolfram Syndrome (WS) is controversial and optic neuropathy, a cardinal clinical manifestation, is poorly characterized. We here describe the histopathological features in postmortem retinas and optic nerves (ONs) from one patient with WS testing the hypothesis that mitochondrial dysfunction underlies the pathology. Eyes and retrobulbar ONs were obtained at autopsy from a WS patient, and compared with those of a Leber hereditary optic neuropathy (LHON) patient and one healthy control. Retinas were stained with hematoxylin & eosin for general morphology and ONs were immunostained for myelin basic protein (MBP). Immunostained ONs were examined in four "quadrants": superior, inferior, nasal, and temporal. The WS retinas displayed a severe loss of retinal ganglion cells in the macular region similar to the LHON retina, but not in the control. The WS ONs, immunostained for MBP, revealed a zone of degeneration in the inferior and temporal quadrants. This pattern was similar to that seen in the LHON ONs but not in the control. Thus, the WS patient displayed a distinct pattern of optic atrophy observed bilaterally in the temporal and inferior quadrants of the ONs. This arrangement of axonal degeneration, involving primarily the papillomacular bundle, closely resembled LHON and other mitochondrial optic neuropathies, supporting that mitochondrial dysfunction underlies its pathogenesis.
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