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Mutations in the WFS1 Gene Are a Frequent Cause of Autosomal Dominant Nonsyndromic Low-Frequency Hearing Loss in Japanese

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Mutations in the WFS1 Gene Are a Frequent Cause of Autosomal Dominant Nonsyndromic Low-Frequency Hearing Loss in Japanese J Hum Genet (2007) 52:510–515 DOI 10.1007/s10038-007-0144-3 ORIGINAL ARTICLE Mutations in the WFS1 gene are a frequent cause of autosomal dominant nonsyndromic low-frequency hearing loss in Japanese Hisakuni Fukuoka Æ Yukihiko Kanda Æ Shuji Ohta Æ Shin-ichi Usami Received: 14 January 2007 / Accepted: 27 March 2007 / Published online: 11 May 2007 Ó The Japan Society of Human Genetics and Springer 2007 Abstract Mutations in WFS1 are reported to be respon- sites are likely to be mutational hot spots. All three families sible for two conditions with distinct phenotypes; DFNA6/ with WFS1 mutations in this study showed a similar phe- 14/38 and autosomal recessive Wolfram syndrome. They notype, LFSNHL, as in previous reports. In this study, one- differ in their associated symptoms and inheritance mode, third (three out of nine) autosomal dominant LFSNHL and although their most common clinical symptom is families had mutations in the WFS1 gene, indicating that in hearing loss, it is of different types. While DNFA6/14/38 is non-syndromic hearing loss WFS1 is restrictively and characterized by low frequency sensorineural hearing loss commonly found within autosomal dominant LFSNHL (LFSNHL), in contrast, Wolfram syndrome is associated families. with various hearing severities ranging from normal to profound hearing loss that is dissimilar to LFSNHL (Pen- Keywords WSF1 Á Low-frequency hearing loss Á nings et al. 2002). To confirm whether within non-syn- DFNA6/14/38 dromic hearing loss patients WFS1 mutations are found restrictively in patients with LFSNHL and to summarize the mutation spectrum of WFS1 found in Japanese, we Introduction screened 206 Japanese autosomal dominant and 64 auto- somal recessive (sporadic) non-syndromic hearing loss WFS1 is a gene encoding an 890 amino-acid glycoprotein probands with various severities of hearing loss. We found (wolframin), predominantly localized in the endoplasmic three independent autosomal dominant families associated reticulum. Mutations in WFS1 are reported to be respon- with two different WFS1 mutations, A716T and E864K, sible for both non-syndromic and syndromic forms of previously detected in families with European ancestry. hearing loss: autosomal dominant low-frequency sensori- Identification of the same mutations in independent fami- neural hearing loss (LFSNHL) DFNA6/14/38, as well as lies with different racial backgrounds suggests that both autosomal recessive Wolfram syndrome. Both conditions are distinct with regard to phenotype, not only in associated symptoms and inheritance mode, but also in their mutual & H. Fukuoka Á S. Usami ( ) clinical symptom of hearing loss, which is manifested by Department of Otorhinolaryngology, Shinshu University School of Medicine, different types. LFSNHL DFNA6/14/38 is a rare, but 3-1-1 Asahi, Matsumoto 390-8621, Japan clearly differentiated type of hearing loss affecting the low e-mail: [email protected] frequencies (2,000 Hz and below) that worsens over time, but does not progress to profound deafness. Wolfram Y. Kanda Kanda ENT Clinic, 4-25 Wakakusa-cho, syndrome is characterized by diabetes mellitus, diabetes Nagasaki 852-8023, Japan insipidus, optic atrophy (Strom et al. 1998; Inoue et al. 1998) and normal or high/all frequency hearing loss with S. Ohta various hearing severities ranging from mild to profound Aomori Prefectural Hospital, 2-1-1 Higashi-Tsukurimichi, (Pennings et al. 2004). Since WFS1 mutations have been Aomori 030-8553, Japan found in various types of hearing loss, it was an interesting 123 J Hum Genet (2007) 52:510–515 511 question whether WFS1 mutations could be found in non- The control group consisted of 86 unrelated Japanese syndromic hearing loss patients with other than LFSNHL, individuals with normal hearing evaluated by auditory but there had been no reports of mutation screening for testing. All subjects gave prior informed consent for par- various phenotypes of hearing. ticipation in the project, and the Ethical Committee of Twenty-six heterozygous WFS1 mutations for non-syn- Shinshu University approved the study. dromic hearing loss and 110 WFS1 mutations for Wolfram syndrome have been identified. Mutation spectrums of Mutation analysis deafness genes, including GJB2 and SLC26A4, have been shown to be dependent on ethnic background (Ohtsuka All eight exons and flanking intronic sequences except for et al. 2003; Tsukamoto et al. 2003), and therefore whether exon 1 of the WFS1 gene were amplified by polymerase there is a unique WFS1 mutation spectrum in Japanese chain reaction PCR. Primers were designed to flank all of (most probably representative of other Asian populations) the exon–intron boundaries through use of the Primer3 web- was also of interest. based server (http://www-genome.wi.mi.edu/cgi-bin/pri- The present study was carried out to (1) confirm the mer/primer3_www.cgi). Each genomic DNA sample phenotype (whether within non-syndromic hearing loss (40 ng) was amplified using Ex-Taq polymerase (Takara) patients WFS1 mutations are found restrictively in those for 5 min at 95°C, followed by 37 three-step cycles of 95°C with LFSNHL) and (2) summarize the mutation spectrum for 30 s, 56–63°C for 30 s and 72°C for 1.5 min, with a of WFS1 found in Japanese. To do so, we screened 206 final extension at 72°C for 10 min, ending with a holding Japanese autosomal dominant and 64 autosomal recessive period at 4°C in a Perkin-Elmer thermal cycler. The PCR (sporadic) non-syndromic hearing loss probands with var- products varied in size at about 200–700 bp, and they were ious severities of hearing loss. treated with 0.1 ll exonuclease I (Amersham) and 1 ll shrimp alkaline phosphatase (Amersham) and by incubation at 37°C for 30 min, and inactivation at 80°C for 15 min. Materials and methods After the products were purified, we performed standard cycle sequencing reaction with ABI Big Dye terminators in Subjects an ABI 3100 autosequencer (Applied Biosystems). Two-hundred and six Japanese autosomal dominant (AD; Results with two or more generations affected) and 64 autosomal recessive (AR; normal hearing parents and more than two Direct DNA sequencing identified two disease-causing affected siblings or recessive compatible sporadic cases) mutations from AD families (Fig. 1), however no mutations sensorineural hearing loss patients were screened for were found in AR families. Twenty-eight polymorphisms mutations in the WFS1 gene. All probands were from were found among the studied subjects (Table 1). Family #1 independent families, and none had any other associated had a heterozygous G fi A transition at nucleotide 2,146 neurological signs, visual dysfunction or diabetes mellitus. in exon 8, which results in an alanine-to-threonine substi- Severity of hearing loss was classified by a pure-tone tution at codon 716 (A716T). Families #2 and #3 had a average over 500, 1,000, 2,000 and 4,000 Hz in the better heterozygous G fi A transition at nucleotide 2,590 in hearing ears as follows: normal hearing, <20 dB; mild exon 8, which results in a glutamic acid-to-lysine substi- hearing loss, 21–40 dB; moderate hearing loss, 41–70 dB; tution at codon 864 (E864K). Genetic analysis showed co- severe hearing loss, 71–95 dB; and profound hearing loss, segregation of E864K with LFSNHL in the family members greater than 95 dB (GENDEAF 2004). The severity of available to be examined. In contrast, none of the 86 normal hearing loss was classified from normal to profound: nor- controls had these mutations. All of the patients with WFS1 mal (only limited frequencies involved) in 12/0 patients mutations showed dominant inherited LFSNHL, and (<20 dB), mild (21–40 dB) in 43/12 (21/19%), moderate mutations were not found in dominant families with other (41–70 dB) in 96/16 (47/25%), severe (71–95 dB) in 32/9 types of hearing loss or recessive/sporadic families. One- (16/14%) and profound (>95 dB) in 23/27 (11/42%) third (three out of nine) autosomal dominant LFSNHL (dominant/recessive respectively). The age of onset varied families had mutations in the WFS1 gene. from congenital to 60/50 years (dominant/recessive respectively). The type of hearing loss was low frequency (2,000 Hz and below) involved in 9/3 patients (4/5%), high Discussion frequency (2,000 Hz and above) involved in 14/12 patients (7/19%), and all frequencies involved in 183/49 patients We found three independent autosomal dominant families (89/76%) (dominant/recessive, respectively). associated with two different WFS1 mutations. All patients 123 512 J Hum Genet (2007) 52:510–515 Fig. 1 Pedigrees of three families and individual sequence summaries. Overlapped audiogram of nine subjects with WFS1 mutations showing low-frequency hearing loss showed LFSNHL as previously reported in DFNA6/14/38 children in families with a strong history of dominant (Bespalova et al. 2001; Young et al. 2001; Eiberg et al. LFSNHL. In the subjects of this study, hearing loss was 2006). WFS1 mutations were not found in recessive fami- noticed between 5 and 14 years old (mean: 10 years old), lies (even in the patients with lower frequency involved and three of nine patients used hearing aids. In DNFA6/14/ hearing loss), nor in other types of hearing loss, indicating 38 there is no or only mild progression of hearing loss. that in non-syndromic form of hearing loss they can be Some patients have also reported tinnitus, but none re- found only in dominant families with LFSNHL. Despite ported vertigo or dizziness (Young et al. 2001; Lesperance the recent considerable advances in the discovery of et al. 2003; Pennings et al. 2003). In the present study, two deafness genes, clinical application still entails difficulties out of nine patients noticed tinnitus, but none had pro- because of the genetic heterogeneity of deafness.
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