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H-J Park,
S Shaukat,
X-Z Liu,
S H Hahn,
S Naz,
M Ghosh,
H-N Kim,
S-K Moon, S Abe,
K Tukamoto,
S Riazuddin,
M Kabra,
R Erdenetungalag,
J Radnaabazar,
S Khan,
A Pandya,
S-I Usami,
W E Nance,
E R Wilcox,
A J Griffith
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ABSTRACT: Recessive mutations of SLC26A4 (PDS) are a common cause of Pendred syndrome and non-syndromic deafness in western populations. Although south and east Asia contain nearly one half of the global population, the origins and frequencies of SLC26A4 mutations in these regions are unknown. We PCR amplified and sequenced seven exons of SLC26A4 to detect selected mutations in 274 deaf probands from Korea, China, and Mongolia. A total of nine different mutations of SLC26A4 were detected among 15 (5.5%) of the 274 probands. Five mutations were novel and the other four had seldom, if ever, been identified outside east Asia. To identify mutations in south Asians, 212 Pakistani and 106 Indian families with three or more affected offspring of consanguineous matings were analysed for cosegregation of recessive deafness with short tandem repeat markers linked to SLC26A4. All 21 SLC26A4 exons were PCR amplified and sequenced in families segregating SLC26A4 linked deafness. Eleven mutant alleles of SLC26A4 were identified among 17 (5.4%) of the 318 families, and all 11 alleles were novel. SLC26A4 linked haplotypes on chromosomes with recurrent mutations were consistent with founder effects. Our observation of a diverse allelic series unique to each ethnic group indicates that mutational events at SLC26A4 are common and account for approximately 5% of recessive deafness in south Asians and other populations.
Journal of Medical Genetics 05/2003; 40(4):242-8. · 6.36 Impact Factor
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ABSTRACT: We report a high prevalence of GJB2 heterozygous mutations in patients bearing the 1555A-->G mitochondrial mutation, and describe a family in which potential interaction between GJB2 and a mitochondrial gene appears to be the cause of hearing impairment. Patients who are heterozygotes for the GJB2 mutant allele show hearing loss more severe than that seen in sibs lacking a mutant GJB2 allele, suggesting that heterozygous GJB2 mutations may synergistically cause hearing loss when in the presence of a 1555A-->G mutation. The present findings indicate that GJB2 mutations may sometimes be an aggravating factor, in addition to aminoglycoside antibiotics, in the phenotypic expression of the non-syndromic hearing loss associated with the 1555A-->G mitochondrial mutation.
American Journal of Medical Genetics 12/2001; 103(4):334-8.
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ABSTRACT: Sixteen Japanese nonsyndromic autosomal dominant sensorineural hearing loss (ADSNHL) families were investigated clinically as well as genetically. Most families showed postlingual hearing loss. Although the severity of their hearing loss varied, most patients showed mild-moderate sensorineural hearing loss of a progressive nature. Mutation analysis was performed for the MYO7A, KCNQ4, and GJB3 genes, which are known to be responsible for autosomal dominant sensorineural hearing loss. The present study reports that a mutation in KCNQ4, a member of a large family of potassium channel genes, was responsible for ADSNHL in one Japanese family.
Journal of Human Genetics 02/2001; 46(7):355-61. · 2.57 Impact Factor
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ABSTRACT: Mutation analysis of the PDS gene and the EYA1 gene, which are reported to be responsible for hearing loss associated with ear anomalies, was performed in 24 deaf patients with various middle and inner ear anomalies. The present study was done to clarify the spectrum of middle and inner ear malformations covered by these two genes. PDS mutations were found only in patients with enlarged vestibular aqueducts and EYA1 mutations were detected only in patients with ear pits and cervical fistulae, indicating that these two genes are associated with particular forms of middle and inner ear malformation. The genetic approach provides a strong tool for the diagnosis of hearing loss associated with ear anomalies.
Journal of Human Genetics 02/2001; 46(9):518-21. · 2.57 Impact Factor
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Advances in oto-rhino-laryngology 02/2000; 56:203-11.
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S Usami, S Abe,
J Akita,
A Namba,
H Shinkawa,
M Ishii,
S Iwasaki,
T Hoshino,
J Ito,
K Doi,
T Kubo,
T Nakagawa,
S Komiyama,
T Tono,
S Komune
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ABSTRACT: The frequency of three mitochondrial point mutations, 1555A-->G, 3243A-->G, and 7445A-->G, known to be associated with hearing impairment, was examined using restriction fragment length polymorphism (RFLP) analysis in two Japanese groups: (1) 319 unrelated SNHL outpatients (including 21 with aminoglycoside antibiotic injection history), and (2) 140 cochlear implantation patients (including 22 with aminoglycoside induced hearing loss). Approximately 3% of the outpatients and 10% of the cochlear implantation patients had the 1555A-->G mutation. The frequency was higher in the patients with a history of aminoglycoside injection (outpatient group 33%, cochlear implantation group 59%). One outpatient (0.314%) had the 3243A-->G mutation, but no outpatients had the 7445A-->G mutation and neither were found in the cochlear implantation group. The significance of the 1555A-->G mutation, the most prevalent mitochondrial mutation found in this study of a hearing impaired population in Japan, among subjects with specific backgrounds, such as aminoglycoside induced hearing loss, is evident.
Journal of Medical Genetics 02/2000; 37(1):38-40. · 6.36 Impact Factor
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ABSTRACT: The gene responsible for DNFB1 and DFNA3, connexin 26 (GJB2), was recently identified and more than 20 disease causing mutations have been reported so far. This paper presents mutation analysis for GJB2 in Japanese non-syndromic hearing loss patients compatible with recessive inheritance. It was confirmed that GJB2 mutations are an important cause of hearing loss in this population, with three mutations, 235delC, Y136X, and R143W, especially frequent. Of these three mutations, 235delC was most prevalent at 73%. Surprisingly, the 35delG mutation, which is the most common GJB2 mutation in white subjects, was not found in the present study. Our data indicated that specific combinations of GJB2 mutation exist in different populations.
Journal of Medical Genetics 02/2000; 37(1):41-3. · 6.36 Impact Factor
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ABSTRACT: Mutations in connexin 26 are responsible for approximately 20% of genetic hearing loss and 10% of all childhood hearing loss. However, only about 75% of the mutations predicted to be in Cx26 are actually observed. While this may be due to mutations in noncoding regulatory regions, an alternative hypothesis is that some cases may be due to mutations in another gene immediately adjacent to Cx26. Another gap junction gene, connexin 30 (HGMW-approved symbol GJB6), is found to lie on the same PAC clone that hybridizes to chromosome 13q12. Human connexin 26 and connexin 30 are expressed in the same cells of the cochlea. Cx26 and Cx30 share 77% identity in amino acid sequence but Cx30 has an additional 37 amino acids at its C-terminus. These considerations led us to hypothesize that mutations in Cx30 might also be responsible for hearing loss. Eight-eight recessive nonsyndromic hearing loss families from both American and Japanese populations were screened for mutations. In addition, 23 dominant hearing loss families and 6 singleton families presumed to be recessive were tested. No significant mutation has been found in the dominant or recessive families.
Genomics 12/1999; 62(2):172-6. · 3.02 Impact Factor
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ABSTRACT: Enlarged vestibular aqueduct (EVA), known as the most common form of inner ear abnormality, has recently been of particular genetic interest because this anomaly is inherited in a recessive manner. The locus for non-syndromic sensorineural hearing loss with EVA has been mapped to the same chromosomal region, 7q31, as the Pendred syndrome locus. In the present study, seven mutations in the PDS gene (PDS), the gene responsible for Pendred syndrome, have been found in families of non-syndromic sensorineural hearing loss with EVA. One family is homozygous, three families are compound heterozygotes, and two families are heterozygous but with no other mutation detected. The present results provide evidence that mutations in PDS cause both syndromic and non-syndromic hearing loss.
Human Genetics 03/1999; 104(2):188-92. · 5.07 Impact Factor
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ABSTRACT: The most common form of inner ear abnormality, enlarged vestibular aqueduct (EVA), is of particular interest because it is associated with characteristic clinical findings, including fluctuating and sometimes progressive sensorineural hearing loss and disequilibrium symptoms. Although EVA has been reported to be inherited in a recessive manner, nothing else is known about the genetic basis of this hearing loss. Here we report on the localization of the gene responsible for sensorineural hearing loss associated with EVA to chromosomal region 7q31, with maximum multipoint LOD score of 3.647. The EVA candidate gene region lies in a 1.7-cM interval between the flanking markers D7S501 and D7S2425. Interestingly, this region overlaps the region containing the gene responsible for Pendred syndrome, called PDS, which was identified recently. However, the present subjects did not fulfill the criteria for Pendred syndrome. It is hypothesized that different mutations within the PDS gene may cause different phenotypes ranging from EVA to the Mondini deformity seen in Pendred syndrome.
American Journal of Medical Genetics 03/1999; 82(4):322-8.
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ABSTRACT: Advances in molecular genetics have recently revealed that mutations in the EYA1 gene are responsible for branchio-oto-renal (BOR) syndrome in European and other populations. This is the first report confirming that an EYA1 gene mutation is also disease-causing in an Asian population. We have described one Japanese BOR syndrome family showing a novel mutation in exon 7 of the EYA1 gene. There was extensive variation of clinical phenotypes within this family. When the physician is confronted with a BOR family showing a wide variation in clinical expression, molecular genetic testing helps to achieve accurate diagnosis.
Journal of Human Genetics 02/1999; 44(4):261-5. · 2.57 Impact Factor
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ABSTRACT: The 1555A-->G point mutation is associated with a susceptibility to aminoglycoside antibiotics, and is of particular interest, as it may cause hearing loss even without aminoglycoside exposure. There may be a considerably large high-risk population in Japan, and to avoid possible side effects in this group, a rapid mass screening system and careful counseling are recommended. We are currently using the mutant allele specific amplification (MASA) method to detect the 1555A-->G mitochondrial mutation and we distribute a warning card to subjects found to bear this mutation.
Journal of Human Genetics 02/1999; 44(5):304-7. · 2.57 Impact Factor
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ABSTRACT: This study aimed to describe the performance of a cochlear implant in a patient with profound hearing loss with the A1555G mitochondrial mutation.
The study was conducted at two university hospitals.
A 50-year-old Japanese man in whom bilateral profound hearing loss developed after administration of streptomycin at the age of 23 participated. The pedigree of the family showed exclusively maternal transmission of hearing impairment.
Genetic study and auditory rehabilitation with a cochlear implant were performed.
The A1555G point mutation was identified from the patient's mitochondrial DNA. Since activation of the implant, the patient has been using it successfully with a monosyllable recognition score of 78% using Japanese word lists for speech audiometry.
The current case indicated that cochlear implantation may be a valuable choice of therapy for the patient with profound hearing loss with the A1555G mutation. The excellent auditory performance with a cochlear implant suggests that hearing loss associated with this mutation is primarily caused by insult to the cochlear tissue containing rich mitochondria (i.e., hair cells or stria vascularis or both), not to the cochlear nerve and its central connections.
The American journal of otology 12/1998; 19(6):754-7.
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ABSTRACT: The present report describes three familial cases of recessive hearing loss associated with enlargement of the vestibular aqueduct (EVA). Six siblings from three families showed EVA. The common characteristic of these patients was the presence of congenital, high-frequency, fluctuating sensorineural hearing loss. These cases suggest that EVA may be a useful discriminator between different types of recessive hearing loss.
The Annals of otology, rhinology, and laryngology 01/1998; 106(12):1063-9. · 1.05 Impact Factor
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ABSTRACT: Five Japanese families showing aminoglycoside-induced hearing loss were genetically as well as clinically investigated. A mitochondrial mutation at nucleotide 1555 was found in 28 out of 32 subjects. One hundred American control subjects did not show any evidence of the mutation at nucleotide 1555, suggesting that the 1555 A-->G (A1555G) mitochondrial mutation may be found more frequently among populations in the Asian continent. Many subjects who harbor this mitochondrial mutation exhibit a mild, high-frequency, progressive hearing loss even without aminoglycoside injection. The results presented here appear to support the hypothesis that the A1555G mutation may play a more general role in causing hearing loss.
The Laryngoscope 04/1997; 107(4):483-90. · 1.75 Impact Factor
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ABSTRACT: Thirteen Japanese families (ten of which were from the northern part of Japan), with sensorineural hearing loss associated with the 1555 A to G (A1555G) mitochondrial mutation, a known cause of non-syndromic hearing loss, were phylogenetically analysed using data obtained by restriction fragment length polymorphism (RFLP) and D-loop sequencing of mitochondrial DNA (mtDNA). Various types of mtDNA polymorphism were detected by restriction enzymes and D-loop sequence. No common polymorphic pattern throughout the 13 families was found, though three families exhibited the same restriction patterns and the same sequence substitution in the D-loop. To find where each of the 13 families are situated in the phylogenetic tree, the 482-bp of D-loop sequence were compared with those of 62 normal Japanese subjects. Despite the three families mentioned above appearing to be clustered, the remaining 10 families were scattered along the phylogenetic tree. This indicates that there was no common ancestor for the 13 Japanese families bearing the A1555G mutation except three families, and that the A1555G mutation occurred sporadically and multiplied through evolution of the mtDNA in Japan. The present results showed that the common pathogenicity (hearing loss associated with the A1555G mutation) can occur sporadically in families which have different genetic backgrounds, even in the Japanese population.
European Journal of HumanGenetics 6(6):563-9. · 4.40 Impact Factor
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ABSTRACT: Mutations in mitochondrial DNA, which are maternally inherited, have been thought to be one of the causes of sensorineural hearing loss. Two mitochondrial mutational sites (A1555G, A7445G) have been reported to be responsible for non-syndromic hearing impairments. The A1555G mutation causes increased susceptibility to aminoglycoside antibiotic-induced hearing loss as well as non-syndromic sensorineural hearing loss. Our wide screening study showed that there may be a great number of subjects within the Japanese population who have the A1555G mutation. Recent reports suggest that high-risk populations may exist throughout the world. The aminoglycoside-induced hearing loss associated with a mitochondrial mutation is commonly bilateral, symmetric, high frequency involved, and is sometimes associated with progressive sensorineural hearing loss.
Journal of Communication Disorders 31(5):423-34; quiz 434-5. · 1.76 Impact Factor
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ABSTRACT: A mitochondrial mutation at nucleotide 1555 has been reported to be susceptible to aminoglycoside antibiotics as well as one of the causes of nonsyndromic sensorineural hearing loss. We herewith report 2 cases bearing the 1555 A-->G mitochondrial mutation who had hearing loss after short-term exposure to the new aminoglycoside antibiotic, isepamicin sulfate. Even when using aminoglycoside antibiotics with milder side effects, careful attention should be paid in applying them to patients with particular genetic backgrounds.
ORL 60(3):164-9. · 0.91 Impact Factor
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ABSTRACT: Recent genetic studies have shown that hereditary susceptibility to aminoglycoside antibiotics is caused by the 1555 A-->G mitochondrial mutation. We found the 1555 mutation in 4 out of 68 postlingual deaf patients who were candidates for cochlear implantation. All 4 patients developed bilateral profound hearing loss following administration of aminoglycosides. The pedigree of the family shows exclusively maternal transmission of hearing impairment in each case. On comparison with neuro-otological findings from aminoglycoside-induced deaf patients without the 1555 mutation, four distinct characteristics were noted: (1) a progressive nature of hearing loss; (2) better residual pure-tone thresholds; (3) lower thresholds for electrical promontory stimulation, and (4) well-preserved vestibular function. Although other factors such as differing dosages and/or administration routes may also be involved, profound hearing loss associated with the 1555 mutation may be due to a different pathogenic mechanism, i.e., strial dysfunction rather than a direct insult to the hair cells.
ORL 63(1):25-30. · 0.91 Impact Factor
