Frequency of mitochondrial m.1555A > G mutation in Syrian patients with non-syndromic hearing impairment

Background

Mitochondrial maternally inherited hearing impairment (HI) appears to be increasing in frequency. The incidence of mitochondrial defects causing HI is estimated to be between 6 and 33% of all hearing deficiencies. Mitochondrial m.1555A?>?G mutation is the first mtDNA mutation associated with non-syndromic sensorineural deafness and also with aminoglycoside induced HI. Its prevalence varied geographically between different populations.

Methods

We carried out PCR, restriction enzyme based screening, and sequencing of 337 subjects (including 132 patients diagnosed clinically with hereditary deafness) from 54 families from Syria for m.1555A?>?G mitochondrial mutation.

Results

Mitochondrial m.1555A?>?G mutation was detected in one of fifty-four families (1.85%), six out of the 132 (4.5%) of all patients with NSHI and one propositus of the 205 individuals with normal hearing (0.48%).

Conclusion

This is the first study to report prelingual deafness causative gene mutations identified by sequencing technology in Syrian families. It is obvious from the results that the testing for the m.1555A?>?G mutation is useful for diagnosis of hearing loss in Syrian patients and should also be considered prior to treatment with aminoglycosides in predisposed individuals.

     

gjb2 mutation spectrum in inner mongolia and its comparison with other asian populations

Mutations in the GJB2 gene are the most frequently found mutations in patients with nonsyndromic hearing impairment. However, the mutation spectrum and prevalence of mutations vary among different ethnic groups. Every year, 30,000 babies are born with congenital hearing impairment in China. In order to provide appro-pilate genetic testing and counseling to the family, we investigated the molecular etiology of nonsyndromic deafness in 135 unrelated school children attending Chifeng Municipal Special Education School in Inner Mongolia, China. The coding exon of the GJB2 gene was PCR amplified and sequenced. In addition, the 12S rRNA gene and tRNAser UCN of mitochondrial genome were screened for mutations responsible for hearing impairment. Sixty four GJB2 mu-tant alleles, including 60 confirmed pathogenic alleles and 4 unclassified variants, were identified in 31.1% (42/135) of the subjects. Twenty two subjects carried two pathogenic mutations and 20 subjects carried one mutant allele, in-cluding one subject with one autosomal dominant mutation. The 235delC was the most common mutation account-ing for 65.6%(42/64) GJB2 mutant alleles. When compared to other Asian populations, our subject cohort had high-er frequency of 235delC mutation than the Japanese population. The GJB2 mutant alleles account for 23.7% (64/270) of all chromosomes responsible for nonsyndromic heating impairment. Testing of the 4 most prevalent deleterious frame shift mutations(235delC, 299_300delAT, 176191_del16, and 560_605ins46) in this cohort detect-ed 90% of all GJB2 mutant alleles. These results demonstrate that effective genetic testing of the GJB2 gene for pa-tients and families with nonsyndromic hearing impairment is possible in the Chinese population. Since the most common 309kb GJB6 deletion is not detected and only one 1555 A>G mutation in mitochondrial DNA is detected in our patients, investigation of mutations in other nuclear genes and/or environmental factors responsible for non-syndromic heating impairment in the Chinese population is necessary.     

GJB2 mutation spectrum in deaf population in a typical southeastern area of China

Mutations in GJB2 gene are the most frequently found mutations in patients with nonsyndromic hearing impairment. However, the spectrum and prevalence of mutations in this gene vary among different ethnic groups. In China, 30,000 infants are born with congenital hearing impairment annually. In order to provide appropriate genetic testing and counseling to the families, we investigated the molecular etiology of nonsyndromic deafness in 103 unrelated school children attending Nantong School for the Deaf and Mute in Jiangsu Province, China. The coding exon of the GJB2 gene was PCR amplified and sequenced. Sixty two GJB2 mutant alleles were identified in 35.9% (37/103) of the patients. Twenty five patients carried two pathogenic mutations and 12 patients carried one mutant allele. The 235delC was the most common mutation accounting for 69.4% (43/62) of GJB2 mutant alleles. The GJB2 mutant alleles accounted for 30.1% (62/206) of all chromosomes responsible for nonsyndromic hearing impairment. Testing of the 3 most prevalent deleterious frame shift mutations in this cohort detected 100% of all GJB2 mutant alleles. These results demonstrate that an effective genetic testing of GJB2 gene for patients and families with nonsyndromic hearing impairment is possible.     

Normal hearing in a child with the m.1555A>G mutation despite repeated exposure to aminoglycosides. Has the penetrance of this pharmacogenetic interaction been overestimated?

The mtDNA m.1555A>G mutation causes increased susceptibility to aminoglycoside ototoxicity resulting in significant hearing loss in 100% of reported exposed cases. Genetic and audiological assessments were conducted in a sample of 59 children with cystic fibrosis (CF) undergoing aminoglycoside treatment. Of the two m.1555G patients identified one had severe-profound deafness. Surprisingly, the second m.1555G patient exhibited well-preserved hearing despite repeated exposure. This may be a rare case of intact hearing in an m.1555G individual with aminoglycoside use. Alternatively, its penetrance may have been previously overestimated due to recruitment bias. Further studies are required to determine the true penetrance to inform m.1555A>G genetic testing in similar clinical scenarios.     

"中耳微型肺"理论

“中耳微型肺”理论是关于中耳炎发生机制的重要理论，有助于深入理解中耳正常的生理功能，将对指导临床诊断和治疗有重要意义。     

Null Mutation of α<Subscript>1D</Subscript> Ca<Superscript>2+</Superscript> Channel Gene Results in Deafness but No Vestibular Defect in Mice

Multiple Ca²⁺ channels confer diverse functions to hair cells of the auditory and vestibular organs in the mammalian inner ear. We used gene-targeting technology to generate _1D Ca²⁺ channel-deficient mice to determine the physiological role of these Ca²⁺ channels in hearing and balance. Analyses of auditory-evoked brainstem recordings confirmed that _1D^–/– mice were deaf and revealed that heterozygous (_1D^+/–) mice have increased hearing thresholds. However, hearing deficits in _1D^+/– mice were manifested mainly by the increase in threshold of low-frequency sounds. In contrast to impaired hearing, _1D^–/– mice have balance performances equivalent to their wild-type littermates. Light and electron microscope analyses of the inner ear revealed outer hair cell loss at the apical cochlea, but no apparent abnormality at the basal cochlea and the vestibule. We determined the mechanisms underlying the auditory function defects and the normal vestibular functions by examining the Ba²⁺ currents in cochlear inner and outer hair cells versus utricular hair cells in _1D^+/– mice. Whereas the whole-cell Ba²⁺ currents in inner hair cells consist mainly of the nimodipine-sensitive current (~85%), the utricular hair cells express only ~50% of this channel subtype. Thus, differential expression of _1D channels in the cochlear and utricular hair cells confers the phenotype of the _1D null mutant mice. Because vestibular and cochlear hair cells share common features and null deletion of several genes have yielded both deafness and imbalance in mice, _1D null mutant mice may serve as a model to disentangle vestibular from auditory-specific functions.     

"婴幼儿听力学最新发展"国际会议纪要

“婴幼儿听力学最新发展”国际会议于2004年12月3～5曰在香港召开，来自中国、美国、菲律宾、泰国、马来西亚、日本、澳大利亚、瑞典等14个国家及地区的听力学家、耳鼻咽喉科、儿科医师、言语一语言病理学家、聋儿教育学家以及听力科技专业人员400余人，内地专家100余人参加了这一盛会。