| Full gene name: | Wolfram syndrome 1 (wolframin) |
|---|---|
| Entrez Gene ID: | 7466 |
| Location: | 4p16.1 |
| Synonyms: | WFS, WFSL, WFRS |
| Type: | protein-coding |
SNPs given by the user that are near or inside this gene:
| SNP | Distance (bp) | Direction |
|---|---|---|
| rs10010131 | 0 | within |
This gene encodes a transmembrane protein, which is located primarily in the endoplasmic reticulum and ubiquitously expressed with highest levels in brain, pancreas, heart, and insulinoma beta-cell lines. Mutations in this gene are associated with Wolfram syndrome, also called DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness), an autosomal recessive disorder. The disease affects the brain and central nervous system. Mutations in this gene can also cause autosomal dominant deafness 6 (DFNA6), also known as DFNA14 or DFNA38. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Mar 2009]
| OMIM ID: | `OMIM ID 606201 `_ |
|---|
Allelic Variants (Selected Examples)
.0001 WOLFRAM SYNDROME 1
In 3 affected sibs with Wolfram syndrome (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.
.0002 WOLFRAM SYNDROME 1
In a consanguineous Japanese family segregating Wolfram syndrome (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.
.0003 WOLFRAM SYNDROME 1
In a Japanese family segregating Wolfram syndrome (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.
.0004 WOLFRAM SYNDROME 1
In a European family, Inoue et al. (1998) demonstrated that 3 sibs with Wolfram syndrome (222300) were compound heterozygotes 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) truncation of the protein, predicted to lack 242 amino acids of the C terminus (inherited from the mother).
.0005 WOLFRAM SYNDROME 1
See 222300.0004 and Inoue et al. (1998).
.0006 WOLFRAM SYNDROME 1
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 (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.
.0007 WOLFRAM SYNDROME 1
In a 10-year-old Saudi Arabian child with Wolfram syndrome (222300) and 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.
.0008 WOLFRAM SYNDROME 1
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 (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.
.0009 WOLFRAM SYNDROME 1
In a brother and sister with Wolfram syndrome (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.
.0010 WOLFRAM SYNDROME 1
In a 25-year-old female patient with Wolfram syndrome (222300), Strom et al. (1998) found compound heterozygosity for 2 nonsense mutations, gln226 to ter and gln819 to ter (222300.0011) of the WFS1 gene. These mutations were located in exons 6 and 8, respectively. diabetes mellitus and diabetes insipidus had their onset at 7 years of age; progressive optic atrophy began at 9 years, abnormal audiogram at 22 years, and renal tract abnormalities at 24 years. The patient also had ataxia and nystagmus.
.0011 WOLFRAM SYNDROME 1
See 222300.0010 and Strom et al. (1998).
.0012 WOLFRAM SYNDROME 1
Hardy et al. (1999) and Sam et al. (2001) described Wolfram syndrome (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.
.0013 WOLFRAM SYNDROME 1
Gomez-Zaera et al. (2001) studied 22 Wolfram syndrome (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).
.0014 DEAFNESS, AUTOSOMAL DOMINANT 6
Young et al. (2001) described a 6-generation Canadian family with dominantly inherited progressive hearing loss (600965), in which affected individuals were heterozygous for a 2146G-A transition in WFS1. The mutation resulted in an ala716-to-thr 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.
.0015 DEAFNESS, AUTOSOMAL DOMINANT 6
Bespalova et al. (2001) described a 3-generation American family with low-frequency sensorineural hearing loss (600965). Affected individuals were heterozygous for a T2656C transition in the WFS1 gene, resulting in a leu829-to-pro (L829P) substitution.
.0016 DEAFNESS, AUTOSOMAL DOMINANT 6
Bespalova et al. (2001) and Cryns et al. (2002) described patients with low-frequency sensorineural hearing loss (600965) due to a 2096C-T nucleotide change in exon 8 of the WFS1 gene, predicting a thr699-to-met (T699M) protein change.
.0017 DEAFNESS, AUTOSOMAL DOMINANT 6
Bespalova et al. (2001) and Cryns et al. (2002) described patients with low-frequency sensorineural hearing loss (600965) due to a 2492G-A transition in exon 8 of the WFS1 gene, predicting a gly831-to-asp (G831D) amino acid change.
.0018 DEAFNESS, AUTOSOMAL DOMINANT 6
In a Japanese family in which 20 members had nonsyndromic low-frequency sensorineural hearing loss (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).
.0019 WOLFRAM SYNDROME 1
In Wolfram syndrome (222300) patients from 5 different unrelated Italian families, Colosimo et al. (2003) found a 16-bp deletion that removed nucleotides 1362 to 1377, causing a frameshift with premature termination at codon 454.
.0020 WOLFRAM-LIKE SYNDROME, AUTOSOMAL DOMINANT
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 (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 WSF1 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 WSF1, resulting in an arg228-to-gln (R228Q; 606201.0026) substitution at a conserved residue that was not found in controls.
.0021 diabetes MELLITUS, NONinsulin-DEPENDENT, ASSOCIATION WITH
In an association study for type 2 diabetes (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 (602228.0022), 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.
.0022 diabetes MELLITUS, NONinsulin-DEPENDENT, ASSOCIATION WITH
See 602228.0021 and Sandhu et al. (2007).
.0023 DEAFNESS, AUTOSOMAL DOMINANT 6
In 6 affected members of a family with autosomal dominant sensorineural deafness (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.
.0024 WOLFRAM SYNDROME 1
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 truncation. 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 truncation. 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.
.0025 WOLFRAM SYNDROME 1
See 606201.0024 and Zalloua et al. (2008).
.0026 WOLFRAM-LIKE SYNDROME, AUTOSOMAL DOMINANT
See 606201.0020 and Valero et al. (2008).
.0027 WOLFRAM-LIKE SYNDROME, AUTOSOMAL DOMINANT
In 3 affected members of a Dutch family segregating autosomal dominant deafness and optic neuropathy (Wolfram-like syndrome; 614296), Hogewind et al. (2010) identified heterozygosity for a 2508G-C transversion in exon 8 of the WSF1 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.
.0028 WOLFRAM-LIKE SYNDROME, AUTOSOMAL DOMINANT
In affected members of 6 unrelated families segregating autosomal dominant hearing loss and optic atrophy (Wolfram-like syndrome; 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 (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.
.0029 WOLFRAM SYNDROME 1
See 606201.0028 and Rendtorff et al. (2011).
.0030 WOLFRAM SYNDROME 1
See 606201.0028 and Tessa et al. (2001).
.0031 WOLFRAM-LIKE SYNDROME, AUTOSOMAL DOMINANT
In a sister and brother and their affected mother from a Caucasian UK family segregating autosomal dominant hearing loss and optic atrophy (Wolfram-like syndrome; 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.
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