Alternative titles; symbols
HGNC Approved Gene Symbol: WFS1
Cytogenetic location: 4p16.1 Genomic coordinates (GRCh38) : 4:6,269,850-6,303,265 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4p16.1 | ?Cataract 41 | 116400 | Autosomal dominant | 3 |
| {Diabetes mellitus, noninsulin-dependent, association with} | 125853 | Autosomal dominant | 3 | |
| Deafness, autosomal dominant 6/14/38 | 600965 | Autosomal dominant | 3 | |
| Wolfram syndrome 1 | 222300 | Autosomal recessive | 3 | |
| Wolfram-like syndrome, autosomal dominant | 614296 | Autosomal dominant | 3 |
Strom et al. (1998) screened 4 candidate genes in a refined critical linkage interval for Wolfram syndrome (WFS1; 222300) on chromosome 4p16. One of these genes, WFS1, which they called 'wolframin,' codes for a predicted 890-amino acid transmembrane protein with a calculated molecular mass of about 100 kD. WFS1 was predicted to have 9 central transmembrane domains, with an extracytoplasmic N terminus and an intracytoplasmic C terminus. Human WFS1 shares 87% amino acid identity with its mouse homolog. Northern blot analysis detected a 3.6-kb transcript in all human tissues examined. Expression was strong in heart, intermediate in brain, placenta, lung, and pancreas, and weak in liver, skeletal muscle, and kidney.
Independently, Inoue et al. (1998) positionally cloned the WFS1 gene. They obtained the full-length cDNA by screening an infant brain cDNA library, followed by 5-prime RACE. The WFS1 hydrophobicity curve suggested the presence of approximately 10 transmembrane segments in WFS1. Northern blot analysis detected a major transcript of 3.7 kb in all human tissues examined, including pancreas. Northern blot analysis of total RNA showed high expression of WFS1 in pancreatic islets compared with exocrine pancreas.
Hofmann et al. (2003) reported that wolframin is ubiquitously expressed, with highest levels in brain, pancreas, heart, and insulinoma beta-cell lines. Wolframin assembled into higher molecular weight complexes of 400 kD in the membrane, and N-glycosylation was essential for its biogenesis and stability.
By Western blot, Berry et al. (2013) demonstrated expression of Wfs1 in whole mouse eye at embryonic day 18.5 (E18.5) and in whole lens tissue extract at postnatal days 3 and 21. Immunocytochemistry demonstrated high-level expression of Wfs1 in the developing mouse lens at E18.5, but not at E12.5.
Inoue et al. (1998) found that the WFS1 gene contains 8 exons, spanning 33.4 kb of genomic DNA.
By genomic sequence analysis, Strom et al. (1998) mapped the WFS1 gene to chromosome 4p16.
Using biochemical methods, Takeda et al. (2001) showed that the WFS1 protein is an integral, endoglycosidase H-sensitive membrane glycoprotein that localizes primarily in the endoplasmic reticulum (ER). Immunofluorescence staining of overexpressed WFS1 in transiently transfected COS-7 cells showed a characteristic reticular pattern over the cytoplasm and overlapped with ER marker staining. In rat brain, at both the protein and mRNA level, WFS1 was present predominantly in selected neurons in the hippocampus CA1, amygdaloid areas, olfactory tubercle, and superficial layer of the allocortex.
Osman et al. (2003) found that human WFS1 expressed in Xenopus oocytes localized to the ER. Planar oocyte lipid bilayers containing WFS1 showed a large cation-selective channel activity that was blocked by Mg(2+) or Ca(2+). Fused bilayers containing WFS1 showed an elevated slope conductance following activation by inositol 1,4,5-triphosphate. Osman et al. (2003) proposed that WFS1 functions as an ER calcium channel or as a regulator of ER calcium channel activity.
Using real-time PCR, Fonseca et al. (2005) found that Wfs1 was induced by ER stress in mouse fibroblasts and that its expression was controlled by Ire1-alpha (ERN1; 604033) and Perk (EIF2AK3; 604032), which are involved in the unfolded protein response. Expression of Wfs1 was upregulated in mouse islets during glucose-induced insulin secretion, and knockdown of Wfs1 in mouse beta cells resulted in ER stress and cell dysfunction. Fonseca et al. (2005) hypothesized that Wolfram syndrome involves chronic ER stress in pancreatic beta cells.
Using yeast 2-hybrid analysis, Zatyka et al. (2008) found that the C-terminal domain of WFS1, which is positioned in the ER lumen, bound the C-terminal domain of the ER-localized Na+/K+ ATPase beta-1 subunit (ATP1B1; 182330). The interaction was confirmed by reciprocal coimmunoprecipitation analysis of proteins expressed in transfected COS-7 cells and endogenous proteins in human and mouse cell lines. Wolfram syndrome patient fibroblasts with 2 different WFS1 mutations showed reduced ATP1B1 levels. Conversely, knockdown of Atp1b1 expression in a mouse insulinoma cell line led to reduced Wfs1 expression. Zatyka et al. (2008) concluded that interaction with WFS1 may be important for ATP1B1 maturation in the ER and that loss of this interaction may contribute to the pathology seen in Wolfram syndrome.
Wolfram Syndrome 1
Strom et al. (1998) identified loss-of-function mutations in both alleles of the WFS1 gene in patients with Wolfram syndrome-1 (WFS1; 222300). Homozygous mutations were found in 5 families; compound heterozygosity was found in 3 other families. In a ninth family, only a heterozygous stop mutation was found. No mutations in either allele were detected in 3 other families. One of the families was reportedly consanguineous but no mutations were detected in that family. Mutations in exon 1, which was not included in the mutation screen, intronic mutations including deletions, or mutations in the regulatory flanking regions of the gene could be pathogenic in these families.
Hardy et al. (1999) performed direct DNA sequencing to screen the entire coding region of the WFS1 gene in 30 patients from 19 British kindreds with Wolfram syndrome. DNA was also screened for structural rearrangements (deletions and duplications) and point mutations in mtDNA. No pathogenic mtDNA mutations were found in this cohort. The authors identified 24 mutations in the WFS1 gene: 8 nonsense mutations, 8 missense mutations, 3 in-frame deletions, 1 in-frame insertion, and 4 frameshift mutations. Of these, 23 were novel mutations, and most occurred in exon 8. Most patients were compound heterozygotes for 2 mutations, and there was no common founder mutation. The data were also analyzed for genotype-phenotype relationships. Although some interesting cases were noted, consideration of the small sample size and frequency of each mutation indicated no clear-cut correlations between any of the observed mutations and disease severity. There were no obvious mutation hotspots or clusters.
Khanim et al. (2001) stated that mutation analysis of the WFS1 gene had identified mutations in 90% of patients with Wolfram syndrome. Most were compound heterozygotes with private mutations distributed throughout the gene with no obvious hotspots.
Colosimo et al. (2003) identified 19 different mutations in the WFS1 gene in a study of 19 Italian patients with Wolfram syndrome. Mutations were found in 18 of the 19 patients (95%). All of the mutations except 1 were novel, were preferentially located in WFS1 exon 8, and included deletions, insertions, duplications, and nonsense and missense changes. In particular, a 16-bp deletion in WFS1 codon 454 (606201.0019) was detected in 5 different unrelated nuclear families, being the most prevalent alteration in these Italian patients.
In a review of the mutational spectrum of the WFS1 gene, Cryns et al. (2003) pointed out that mutations associated with Wolfram syndrome are spread over the entire coding region and are typically inactivating, suggesting that a loss of function causes the disease phenotype. In contrast, only noninactivating mutations have been found in DFNA6/14 families, and these mutations are mainly located in the C-terminal protein domain.
In a study of 6 Spanish families with a total of 7 Wolfram syndrome patients, Domenech et al. (2004) identified 3 previously undescribed mutations in the WFS1 gene as well as the duplication 409dup16 (606201.0013), previously reported as 425ins16 (Gomez-Zaera et al., 2001).
Hansen et al. (2005) identified mutations in the WFS1 gene in 8 affected members of 7 Danish families with Wolfram syndrome. Four of the mutations were novel. Mutations were identified in 11 of 14 disease chromosomes; in 3 families, only 1 mutation was found.
Zalloua et al. (2008) performed family-based linkage analysis followed by systematic screening of WFS1 exons in Lebanese juvenile-onset insulin-dependent diabetes (222100) probands and found homozygous or compound heterozygous WFS1 mutations in 22 (5.5%) of the 399 probands, of whom 17 were diagnosed with WFS and 5 with nonsyndromic nonautoimmune diabetes mellitus. Overall, 38 probands and affected family members were homozygous or compound heterozygous for WFS1 mutations, 11 (29%) of whom were diagnosed with nonsyndromic DM; all of the latter patients carried a complex WFS1 mutation (606201.0024), which the authors designated WFS1(LIB) and which resulted in the delayed onset or absence of extrapancreatic features of WFS. In addition, there were 2 patients with an initial diagnosis of nonsyndromic DM that was revised to WFS when they developed optic atrophy during the course of the study; Zalloua et al. (2008) noted that longer follow-up of the WFS1-mutated nonsyndromic DM patients or a specific study of adult patient populations would be needed to determine whether a subset of the WFS1(LIB) patients are exempted from extrapancreatic manifestations during their lifetime.
Pathophysiology of WFS1 Mutations in Wolfram Syndrome
In a patient carrying both a nonsense (frameshift) and a missense mutation, Hofmann et al. (2003) detected mRNA levels half that of controls; sequencing confirmed that these transcripts were exclusively derived from the missense allele. Transfection experiments with the missense transcript revealed a markedly reduced steady-state level of wolframin and a strongly reduced half-life. Hofmann et al. (2003) concluded that the pathophysiology in Wolfram syndrome in the presence of a missense mutation is likely that of reduced protein dosage rather than dysfunction of the mutant protein.
By analyzing WFS1 patient cells and COS-7 cells expressing 4 missense and 2 truncating mutations in WFS1, Hofmann and Bauer (2006) found that all mutations led to drastically reduced steady-state levels of WFS1 protein. Mutant proteins were highly unstable and were removed by proteasomal degradation. Hofmann and Bauer (2006) concluded that WFS1 mutations cause loss of function by cellular depletion of WFS1.
Autosomal Dominant Nonsyndromic Sensorineural Deafness
Bespalova et al. (2001) defined a subset of nonsyndromic sensorineural hearing loss affecting low frequencies without profound deafness (600965) in which all individuals studied had WFS1 mutations (e.g., 606201.0015). This subset included families that had been linked to loci designated DFNA6 and DFNA14. Bespalova et al. (2001) concluded that mutations in the WFS1 gene are a common cause of sensorineural hearing loss. Additionally, an autosomal dominant sensorineural hearing loss designated DFNA38 was shown to be caused by mutation in the WFS1 gene (606201.0014).
Cryns et al. (2002) stated that only 2 of the more than 70 loci identified as associated with hereditary hearing impairment are associated with an auditory phenotype that predominantly affects the low frequencies: DFNA1 (124900) and DFNA6/14 (600965). Cryns et al. (2002) did mutation screening of the WFS1 gene in 8 autosomal dominant families and 12 sporadic cases in which affected persons had low-frequency sensorineural hearing impairment. They identified 7 missense mutations and a single amino acid deletion affecting conserved amino acids in 6 families and 1 sporadic case, indicating that mutations in WFS1 are a major cause of inherited low-frequency hearing impairment. Among the 10 WFS1 mutations reported in low-frequency sensorineural hearing impairment, none was expected to lead to premature protein termination, and 9 clustered in the C-terminal protein domain. In contrast, 64% of the Wolfram syndrome mutations are inactivating. The results indicated that only noninactivating mutations in WFS1 are responsible for nonsyndromic low-frequency hearing impairment.
Fukuoka et al. (2007) analyzed the WFS1 gene in 206 Japanese autosomal dominant and 64 autosomal recessive (sporadic) nonsyndromic hearing loss probands with varying severities of hearing loss and identified 2 different missense mutations in 3 unrelated families (see 606201.0014 and 606201.0020, respectively). All of the mutation-positive patients had dominantly inherited low-frequency sensorineural hearing loss. Because both mutations had previously been identified in patients of European ancestry, Fukuoka et al. (2007) suggested that the sites are likely to be mutation hotspots.
Autosomal Dominant Wolfram-like Syndrome
Domenech et al. (2002) screened the WFS1 gene in 48 patients with autosomal recessive deafness, 38 patients with type 2 diabetes mellitus (T2D; 125853), and 23 patients with both deafness and T2D. In 3 unrelated patients who had both deafness and diabetes, they identified 3 different heterozygous missense mutations, which were located in the intracytoplasmic domain of the protein and were not detected in 49 healthy controls. Domenech et al. (2002) stated that the lack of knowledge about the function of WFS1 made it difficult to explain the possible contribution of these mutations to the diseases. One of the mutations, V871M, was also found in a patient who had only deafness and was present in her deaf sister, but was detected in her unaffected father. (The V871M variant had previously been detected by Young et al., 2001 in a family with autosomal dominant deafness, but did not segregate with disease in that family; see 606201.0014.)
In a 3-generation Danish family segregating an autosomal dominant Wolfram-like syndrome (WFSL; 614296) in which affected individuals had deafness, optic atrophy, and impaired glucose regulation mapping to chromosome 4p16.3, Eiberg et al. (2006) analyzed the candidate gene WFS1 and identified a missense mutation (E864K; 606201.0020) in affected individuals. The mutation was not found in unaffected family members or in 2 family members who had only isolated congenital hearing impairment.
In a 60-year-old French man with congenital hearing impairment and T2D and his 81-year-old mother with deafness, diabetes, and optic atrophy, both of whom were known to be negative for the common mtDNA mutations associated with the maternally inherited diabetes-deafness syndrome (MIDD; 520000), Valero et al. (2008) identified heterozygosity for the E864K mutation in the WFS1 gene.
In affected members of a Dutch family with deafness and optic neuropathy in whom screening of the OPA1 gene (605290) and mtDNA screening for the 3 most frequent Leber optic atrophy (535000) mutations were both negative, Hogewind et al. (2010) identified heterozygosity for a missense mutation in the WFS1 gene (K836N; 606201.0027).
Rendtorff et al. (2011) analyzed the WFS1 gene in 15 probands with deafness and optic atrophy who were known to be negative for mutation in the OPA1 and TIMM8A (300356) genes, and identified heterozygosity for the same missense mutation in the WFS1 gene (A684V; 606201.0028) in 6 probands. Two additional probands were heterozygous for 2 different WFS1 missense mutations (see, e.g., 606201.0031). In 7 of the 8 mutation-positive families, there were spouses with isolated sensorineural hearing loss (SNHL); analysis of the GJB2 gene (121011) revealed that 3 of the probands who were heterozygous for mutation in WFS1 also carried a known SNHL-related mutation in the GJB2 gene (121011.0001 or 121011.0005), inherited from a deaf parent who did not have optic atrophy.
Cataract 41
In an affected member of a 4-generation family of Irish descent segregating autosomal dominant congenital nuclear cataract mapping to chromosome 4p16.1 (CTRCT41; 116400), Berry et al. (2013) performed exome sequencing and identified heterozygosity for a missense mutation in the WFS1 gene (606201.0032). Direct genomic sequencing confirmed that the mutation cosegregated completely with disease in the family. Screening of the WFS1 gene in a panel of 50 unrelated individuals with autosomal dominant cataract did not reveal any other mutations.
Association with Type 2 Diabetes Mellitus
Sandhu et al. (2007) conducted a gene-centric association study for type 2 diabetes mellitus (T2D; 125853) in multiple large cohorts and identified 2 SNPs located in the WFS1 gene, rs10010131 (606201.0021) and rs6446482 (602201.0022), that were strongly associated with diabetes risk (P = 1.4 x 10(-7) and P = 3.4 x 10(-7), respectively, in the pooled study set). The risk allele was the major allele for both SNPs, with a frequency of 60% for both. The authors noted that both are intronic, with no obvious evidence for biologic function.
Ishihara et al. (2004) disrupted the wfs1 gene in mice. The mutant mice developed glucose intolerance or overt diabetes due to insufficient insulin (see 176730) secretion in vivo. Islets isolated from mutant mice exhibited decreased insulin secretion in response to glucose. The defective insulin secretion was accompanied by reduced cellular calcium responses to the secretagogue. Immunohistochemical analyses demonstrated progressive beta-cell loss in mutant mice, while alpha cells, which barely express WFS1 protein, were preserved. Furthermore, isolated islets from mutant mice exhibited increased apoptosis, at high concentration of glucose or with exposure to endoplasmic reticulum stress inducers. The authors suggested that WFS1 protein may play an important role in both stimulus-secretion coupling for insulin exocytosis and maintenance of beta-cell mass.
In 3 affected sibs with Wolfram syndrome (WFS1; 222300) in a consanguineous Japanese family, Inoue et al. (1998) found a TC deletion at position 2812 in the WFS1 sequence. The deletion was predicted to cause a frameshift at codon 882; they referred to the mutation as del882fs/ter937. The normal stop codon at 891 was absent and a new downstream termination codon had been introduced. The predicted protein contained 937 amino acids, 47 more than the normal protein.
In a consanguineous Japanese family segregating Wolfram syndrome (WFS1; 222300), Inoue et al. (1998) demonstrated that 4 affected sibs were homozygous for a 15-bp deletion in the WFS1 gene resulting in deletion of 5 amino acids, tyr-val-tyr-leu-leu, beginning with residue 508.
In a Japanese family segregating Wolfram syndrome (WFS1; 222300), Inoue et al. (1998) demonstrated that affected members were homozygous for a 2341C-T transition resulting in a pro724-to-leu (P724L) amino acid substitution.
In a European family, Inoue et al. (1998) demonstrated that 3 sibs with Wolfram syndrome (WFS1; 222300) were compound heterozygous for a 2254G-T transversion resulting in a gly695-to-val (G695V) amino acid substitution (inherited from the father); and a 2114G-A transition resulting in a trp648-to-ter (W648X; 606201.0005) termination of the protein, predicted to lack 242 amino acids of the C terminus (inherited from the mother).
For discussion of the trp648-to-ter (W648X) mutation in the WFS1 gene that was found in compound heterozygous state in sibs with Wolfram syndrome (WFS1; 222300) by Inoue et al. (1998), see 606201.0004.
In an Australian family, Inoue et al. (1998) found apparent homozygosity for a 1681C-T transition (pro504 to leu; P504L) of the WFS1 gene in 3 sibs with Wolfram syndrome (WFS1; 222300). The father was shown to be heterozygous for 1681C-T, but the mother was homozygous 1681C. An unaffected child appeared to be homozygous for 1681C. The mother's chromosome 4, inherited by each child, was thought to harbor a microscopic deletion for WFS1, making the affected offspring hemizygous for the P504L mutation.
In a 10-year-old Saudi Arabian child with Wolfram syndrome (WFS1; 222300), born to first-cousin parents, Inoue et al. (1998) found homozygosity for a 7-bp repeat insertion at nucleotide 1610 (CTGAAGG), resulting in a predicted frameshift and premature termination of the protein at codon 544.
Strom et al. (1998) found a 9-bp deletion in exon 8 of the WFS1 gene in a 22-year-old female with Wolfram syndrome (WFS1; 222300). The deletion began at nucleotide 1380, counting from the first base of the start codon, and was present in homozygous state. The patient had onset of diabetes mellitus and diabetes insipidus at 6 years of age and also had progressive optic atrophy, abnormal audiogram, renal tract abnormalities, retarded sexual maturation, ataxia and nystagmus, and depression. A sister with the same mutation had onset of diabetes mellitus at 4 years of age, and at the age of 11 years had renal tract abnormalities as the only additional feature.
In a brother and sister with Wolfram syndrome (WFS1; 222300), Strom et al. (1998) found homozygosity for a splicing mutation in the WFS1 gene: 460+1G-A in the 5-prime splice signal of exon 4. In the brother and sister, diabetes mellitus began at ages 10 and 9 years, progressive optic atrophy at 14 and 12 years, abnormal audiogram at 13 and 17 years, and diabetes insipidus at 15 and 15 years, respectively. Renal tract abnormalities were present only in the brother, who at the age of 17 years showed retarded sexual maturation.
In a 25-year-old female patient with Wolfram syndrome (WFS1; 222300), Strom et al. (1998) found compound heterozygosity for 2 nonsense mutations in the WFS1 gene: gln226 to ter (Q226X) and gln819 to ter (Q819X; 606201.0011). These mutations were located in exons 6 and 8, respectively. The patient had onset of diabetes mellitus and diabetes insipidus at 7 years of age; progressive optic atrophy began at 9 years, abnormal audiogram at 22 years, and renal tract abnormalities at 24 years. She also had ataxia and nystagmus.
For discussion of the gln819-to-ter (Q819X) mutation in the WFS1 gene that was found in compound heterozygous state in a patient with Wolfram syndrome (WFS1; 222300) by Strom et al. (1998), see 606201.0010.
Hardy et al. (1999) and Sam et al. (2001) described Wolfram syndrome (WFS1; 222300) with a distinctive phenotype, namely, central respiratory failure: the patients were homozygous for a 4-bp (TCTT) deletion at position 2648-2651 in exon 8 of the WFS1 gene. The deletion caused loss of codon 883 and a frameshift, producing a 949-amino acid WFS1 protein, which was 59 amino acids longer than normal. The mutation changed the last 7 amino acids of the C terminus of the protein, leaving the transmembrane domains intact. In the patient with the 4-bp deletion reported by Hardy et al. (1999), there was severe brainstem atrophy and central respiratory failure requiring tracheostomy. Her affected sister had died at age 28 from brainstem atrophy and central respiratory failure. Five patients (from 3 families) who were heterozygous for the 4-bp deletion did not have respiratory failure. The 33-year-old patient reported by Sam et al. (2001) was diagnosed as having diabetes mellitus, a neurogenic bladder, and bilateral optic atrophy at the age of 10, 13, and 15, respectively. Audiometry was normal, and there was no evidence of diabetes insipidus. After an episode of respiratory arrest at age 32, she required intubation, ventilation, and subsequently, tracheostomy. MRI scan showed marked brainstem atrophy.
Gomez-Zaera et al. (2001) studied 22 Wolfram syndrome (WFS1; 222300) patients from 16 Spanish families for mutations in the WFS1 coding region by SSCP analysis and direct sequencing. Fifty percent of the pedigrees were found to have a single mutation, 67% in homozygosity and 33% in compound heterozygosity. The authors stated that the mutation is a 16-bp insertion in exon 4 at nucleotide 425 and is predicted to produce an aberrant protein; assuming that no splicing alterations occur, translation will follow until residue 251, where a stop codon is created. The high incidence of this mutation in Spanish families may be explained by a founder effect.
In 4 patients from 3 Spanish families with Wolfram syndrome, Domenech et al. (2004) identified the 425ins16 mutation, which they referred to as a 16-bp duplication (409dup16).
Young et al. (2001) described a 6-generation Canadian family with dominantly inherited progressive hearing loss (DFNA6; 600965), in which affected individuals were heterozygous for a 2146G-A transition in WFS1. The mutation resulted in an ala716-to-thr (A716T) substitution. Affected individuals lacked additional phenotypic features seen in Wolfram syndrome, with the exception of a child who was homozygous for the mutation and also manifested diabetes mellitus by the age of 3 years.
In 2 affected members of a 3-generation Japanese family segregating autosomal dominant nonsyndromic low-frequency sensorineural hearing loss, Fukuoka et al. (2007) identified heterozygosity for the A716T mutation in the WFS1 gene. The mutation was not found in 3 unaffected family members or in 86 controls. Because the same mutation was previously found in a family of European ancestry, the authors suggested that this might represent a mutation hotspot.
Bespalova et al. (2001) described a 3-generation American family with low-frequency sensorineural hearing loss (DFNA6; 600965). Affected individuals were heterozygous for a T2656C transition in the WFS1 gene, resulting in a leu829-to-pro (L829P) substitution.
Bespalova et al. (2001) and Cryns et al. (2002) described patients with low-frequency sensorineural hearing loss (DFNA6; 600965) due to a 2096C-T nucleotide change in exon 8 of the WFS1 gene, predicting a thr699-to-met (T699M) protein change.
Bespalova et al. (2001) and Cryns et al. (2002) described patients with low-frequency sensorineural hearing loss (DFNA6; 600965) due to a 2492G-A transition in exon 8 of the WFS1 gene, predicting a gly831-to-asp (G831D) amino acid change.
In a Japanese family in which 20 members had nonsyndromic low-frequency sensorineural hearing loss (DFNA6; 600965), Komatsu et al. (2002) demonstrated linkage to chromosome 4p16 and found a novel missense mutation, lys634 to thr (K634T), in the WFS1 gene. The mutation was located in the hydrophobic, extracytoplasmic, juxta-transmembrane region of the WFS1 protein. The mutation site was thought to be related to the milder phenotype (lacking tinnitus) in the Japanese family compared with the findings in 6 previously reported patients with WFS1 mutations (Lesperance et al., 1995; Strom et al., 1998).
In Wolfram syndrome (WFS1; 222300) patients from 5 different unrelated Italian families, Colosimo et al. (2003) found a 16-bp deletion in the WFS1 gene that removed nucleotides 1362 to 1377, causing a frameshift with premature termination at codon 454.
In affected members of a 3-generation Danish family with an autosomal dominant Wolfram-like syndrome (WFSL; 614296), Eiberg et al. (2006) identified heterozygosity for a 2590G-A transition in exon 8 of the WFS1 gene, resulting in a glu864-to-lys (E864K) substitution. Affected individuals had optic atrophy, progressive hearing impairment, and impaired glucose regulation. The mutation was not found in unaffected family members, nor in 2 family members with isolated congenital hearing impairment.
In 7 affected members from 2 unrelated Japanese families segregating autosomal dominant nonsyndromic low-frequency sensorineural hearing loss (DFNA6; 600965), Fukuoka et al. (2007) identified heterozygosity for the E864K mutation in the WFS1 gene. The mutation was not found in 3 unaffected family members or in 86 controls. Because the same mutation was previously found in a family of European ancestry, the authors suggested that this might represent a mutation hotspot.
In a 60-year-old French man with congenital hearing impairment and noninsulin-dependent diabetes and his 81-year-old mother with deafness, diabetes, and optic atrophy, Valero et al. (2008) identified heterozygosity for the E864K mutation in the WFS1 gene. The mutation was not found in 100 French controls. The proband, who did not have optic atrophy or any other manifestations of Wolfram syndrome, also carried a 683G-A transition in exon 6 of WFS1, resulting in an arg228-to-gln (R228Q; 606201.0026) substitution at a conserved residue that was not found in controls.
In an association study for type 2 diabetes (T2D; 125853) involving single-nucleotide polymorphisms (SNPs) in genes with roles in pancreatic beta-cell function, Sandhu et al. (2007) identified association of 2 SNPs in the WFS1 gene, rs10010131 and rs6446482 (606201.0022), with diabetes risk. Analysis of a pooled study set of 9,533 cases and 11,389 controls achieved a P value of 1.4 x 10(-7) for rs10010131 and a P value of 3.4 x 10(-7) for rs6446482. Both of these SNPs are intronic, with no obvious evidence for biologic function.
For discussion of the rs6446482 in the WFS1 gene that was found in an association study for type 2 diabetes mellitus (T2D; 125853) by Sandhu et al. (2007), see 606201.0021.
In 6 affected members of a family with autosomal dominant sensorineural deafness (DFNA6; 600965), Hildebrand et al. (2008) identified a heterozygous 2576G-A transition in exon 8 of the WFS1 gene, resulting in an arg859-to-gln (R859Q) substitution in the C-terminal domain. Two affected females had concurrent Crohn disease (see 266600) and Graves disease (275000), respectively. Hildebrand et al. (2008) noted that polymorphisms in the WFS1 gene (see, e.g., 606201.0021) had been associated with autoimmune disease, and suggested that the autoimmune disease in the 2 family members may be related to variants in the WFS1 gene.
In 20 Lebanese patients from 8 families ascertained with juvenile-onset insulin-dependent diabetes (222100), Zalloua et al. (2008) identified homozygosity for a complex mutation in exon 8 of the WFS1 gene, which they designated WFS1(LIB), consisting of a 2289G-A transition, resulting in a val707-to-phe (V707F) substitution, and a 1-bp del (2819delC), resulting in a frameshift predicted to cause premature termination. The mutations were in complete linkage disequilibrium and were consistently associated with the same haplotype. Eight of the 20 patients were diagnosed with Wolfram syndrome (WFS1; 222300), whereas 10 had only nonsyndromic nonautoimmune diabetes mellitus (DM); the remaining 2 patients were given an initial diagnosis of nonsyndromic DM that was revised to WFS when they developed optic atrophy during the course of the study. Another Lebanese patient with nonsyndromic DM was found to be compound heterozygous for the complex mutation and an 8-bp deletion in exon 8 of the WFS1 gene (606201.0025), resulting in a frameshift predicted to cause premature termination. This frameshift mutation (Phe646fs708Ter) was also found in 4 patients with a diagnosis of Wolfram syndrome. Zalloua et al. (2008) noted that follow-up of these WFS1-mutated nonsyndromic DM patients or a specific study of adult patient populations would be needed to determine whether a subset of the WFS1(LIB) patients are exempted from extrapancreatic manifestations during their lifetime.
For discussion of the 8-bp deletion in the WFS1 gene that was found in patients with Wolfram syndrome (WFS1; 222300) or nonsyndromic nonautoimmune diabetes mellitus by Zalloua et al. (2008), see 606201.0024.
For discussion of the arg228-to-gln (R228Q) mutation in the WFS1 gene that was found in compound heterozygous state in a patient with congenital hearing impairment and noninsulin-dependent diabetes (see WFSL, 614296) by Valero et al. (2008), see 606201.0020.
In 3 affected members of a Dutch family segregating autosomal dominant deafness and optic neuropathy (WFSL; 614296), Hogewind et al. (2010) identified heterozygosity for a 2508G-C transversion in exon 8 of the WFS1 gene, resulting in a lys836-to-asn (K836N) substitution at a highly conserved residue within a conserved region of the protein. The mutation was not found in unaffected family members or in 200 European chromosomes.
In affected members of 6 unrelated families segregating autosomal dominant hearing loss and optic atrophy (WFSL; 614296), including the Swedish family originally reported by Samuelson (1940), Rendtorff et al. (2011) identified heterozygosity for a 2051C-T transition in exon 8 of the WFS1 gene, resulting in an ala684-to-val (A684V) substitution at a highly conserved residue in the hydrophilic C terminus. The mutation was not found in 298 ethnically matched control chromosomes. Haplotype analysis suggested that the A684V mutation arose independently in the families studied and may thus represent a mutation hotspot. In 5 of the 6 families, there were spouses with isolated deafness, prompting analysis of the GJB2 gene (121011), which revealed that 2 of the probands also carried known SNHL-related mutations in the GJB2 gene (121011.0001 or 121011.0005) inherited from a deaf parent who did not have optic atrophy. In 1 family, the proband's asymptomatic wife carried a 3-bp deletion (1243delGTC; 606201.0029) in the WFS1 gene, resulting in deletion of val415 (V415del); their 2 children were compound heterozygotes for the deletion and A684V mutation, and both were diagnosed with Wolfram syndrome (WFS1; 222300) based on juvenile-onset diabetes mellitus, optic atrophy, bilateral profound sensorineural hearing loss from birth or infancy, and congenital cataracts. Functional expression analysis in transiently transfected HEK cells demonstrated that both A684V and V415del greatly reduced protein expression compared to wildtype. Rendtorff et al. (2011) noted that A684V had previously been reported in an Italian patient with Wolfram syndrome (Tessa et al., 2001) in compound heterozygosity with a 4-bp deletion (1387delCTCT; 606201.0030) in the WFS1 gene.
For discussion of the 3-bp deletion in the WFS1 gene (1243delGTC) that was found in compound heterozygous state in sibs with Wolfram syndrome (WFS1; 222300) by Rendtorff et al. (2011), see 606201.0028.
For discussion of the 4-bp deletion in the WFS1 gene (1387delCTCT) that was found in compound heterozygous state in a patient with Wolfram syndrome (WFS1; 222300) by Tessa et al. (2001), see 606201.0028.
In a sister and brother and their affected mother from a Caucasian UK family segregating autosomal dominant hearing loss and optic atrophy (WFSL; 614296), Rendtorff et al. (2011) identified heterozygosity for a 2338G-A transition in exon 8 of the WFS1 gene, resulting in a gly780-to-ser (G780S) substitution at a conserved residue in the hydrophilic C terminus. The mutation was not found in 298 ethnically matched control chromosomes, and functional analysis in transiently transfected HEK cells demonstrated that G780S mildly decreased protein expression compared to wildtype. The 14-year-old sister was reported to have bilateral prelingual profound hearing loss and optic atrophy, with normal plasma glucose and urine osmolality, and her 9-year-old affected brother had also been diagnosed with autism. Their 48-year-old affected mother also had schizophrenia and had been treated for psychosis; she had an affected brother and sister. The sibs' father, who had isolated sensorineural hearing loss (SNHL), was homozygous for a known SNHL-related mutation in the GJB2 gene (35delG; 121011.0005), and the sibs were both heterozygous for that mutation as well.
In affected members of a 4-generation family of Irish descent with congenital nuclear cataract (CTRCT41; 116400), Berry et al. (2013) identified heterozygosity for a c.1385A-G transition in exon 8 of the WFS1 gene, resulting in a glu462-to-gly (E462G) substitution at a highly conserved residue in the cytoplasmic loop linking transmembrane domains 4 and 5. The mutation was not found in unaffected family members or in 100 white European controls.
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