11 research outputs found
Evaluation of the Contribution of the <i>EYA4</i> and <i>GRHL2</i> Genes in Korean Patients with Autosomal Dominant Non-Syndromic Hearing Loss
<div><p><i>EYA4</i> and <i>GRHL2</i> encode transcription factors that play an important role in regulating many developmental stages. Since <i>EYA4</i> and <i>GRHL2</i> were identified as the transcription factors for the DFNA10 and DFNA28, 8 <i>EYA4</i> mutations and 2 <i>GRHL2</i> mutations have been reported worldwide. However, these genes have been reported in few studies of the Korean population. In this study, we performed a genetic analysis of <i>EYA4</i> and <i>GRHL</i>2 in 87 unrelated Korean patients with autosomal dominant non-syndromic hearing loss (NSHL). A total of 4 genetic variants in the <i>EYA4</i> gene were identified, including the 2 nonsense mutations p.S288X and p.Q393X. The novel mutation p.Q393X (c.1177C>T) resulted in a change in the codon at amino acid position 393 from a glutamine to a stop codon. The p.Q393X allele was predicted to encode a truncated protein lacking the entire C-terminal Eya homolog region (Eya HR), which is essential for the interaction with the transcription factor SIX3. The p.S288X (c.863C>A) mutation was found in a Korean family from a previous study. We analyzed p.S288X-linked microsatellite markers and determined that p.S288X might be a founder mutation and a hotspot mutation in Koreans. In <i>GRHL2</i>, a total of 4 genetic variants were identified, but none were associated with hearing loss in Korean patients. This suggests that <i>GRHL2</i> may not be a main causal gene for autosomal dominant NSHL in Korean patients. In conclusion, our data provide fundamental information to predict the genotypes of Korean patients diagnosed with autosomal dominant NSHL.</p></div
Molecular and Clinical Characterization of the Variable Phenotype in Korean Families with Hearing Loss Associated with the Mitochondrial A1555G Mutation
<div><p>Hearing loss, which is genetically heterogeneous, can be caused by mutations in the mitochondrial DNA (mtDNA). The A1555G mutation of the 12S ribosomal RNA (rRNA) gene in the mtDNA has been associated with both aminoglycoside-induced and non-syndromic hearing loss in many ethnic populations. Here, we report for the first time the clinical and genetic characterization of nine Korean pedigrees with aminoglycoside-induced and non-syndromic hearing loss. These Korean families carry in the A1555G mutation of 12S rRNA gene and exhibit variable penetrance and expressivity of hearing loss. Specifically, the penetrance of hearing loss in these families ranged between 28.6% and 75%, with an average of 60.8%. These results were higher than the 29.8% penetrance that was previously reported in a Chinese population but similar to the 65.4% and 54.1% penetrance observed in a large Arab-Israeli population and nineteen Spanish pedigrees, respectively. The mutational analysis of the complete mtDNA genome in these families showed that the haplogroups of the Korean population, which belongs to the eastern Asian population, were similar to those of the Chinese population but different from the Spanish population, which belongs to the European-Caucasian population. The mtDNA variants that may act as modifier factors were also found to be similar to the Chinese population. Although the mtDNA haplogroups and variants were similar to the eastern Asian population, we did find some differing phenotypes, although some subjects had the same variants. This result suggests that both the ethnic background and environmental factors lead to a variable phenotype of the A1555G mutation.</p> </div
Summary of <i>EYA4</i> gene mutations identified in previous and current studies.
<p>* N/A, Not available.</p><p>Summary of <i>EYA4</i> gene mutations identified in previous and current studies.</p
Mutation analysis of the <i>EYA4</i> gene in the HL-01 family.
<p>(A) Pedigree of the Korean family with autosomal dominant inheritance (upper panel). A three-generation pedigree including 10 members is presented. The filled symbols and open symbols indicate affected and unaffected individuals, respectively. The arrow designates the proband. Pure tone audiogram for the left and right ears of the HL-01 patient (III-2) (lower panel). The circles and crosses indicate unmasked air conduction thresholds for the right and left ears, respectively. (B) DNA sequencing analysis of <i>EYA4</i> exon 11 shows the c.863C>A change in an affected member (III-2) of the HL-01 family and a normal control. The arrow indicates the changed base. (C) Multiple alignments of the amino acid sequence encoded by the <i>EYA4</i> gene including the VR domain in vertebrate species. The arrow marks the position of the p.S288X mutation.</p
Location of the p.S288X mutation in <i>EYA4</i> and linked STR markers on chromosome 6q.
<p>The physical map marks the location of 5 microsatellite markers and positions.</p
SNPs of the <i>GRHL2</i> gene identified in this study.
<p>SNPs of the <i>GRHL2</i> gene identified in this study.</p
Mutation analysis of the <i>EYA4</i> gene in the YS-151 family.
<p>(A) Pedigree of a Korean family with autosomal dominant inheritance (upper panel). A three-generation pedigree that includes 8 members is presented. The filled symbols and open symbols indicate affected and unaffected individuals, respectively. The arrow designates the proband. Pure tone audiogram for the left and right ears of the YS-151 patient (III-2) (lower panel). The circles and crosses indicate unmasked air conduction thresholds for the right and left ears, respectively. (B) DNA sequencing analysis of <i>EYA4</i> exon 13 shows the c.1177C>T change in an affected family member (III-2) and a normal control. The arrow indicates the changed base. (C) Multiple alignments of the amino acid sequence encoded by the <i>EYA4</i> gene including the HR domain in vertebrate species. The arrow marks the position of the p.Q393X mutation.</p
Air audiograms for pure tone audiometry (PTA) of the available subjects with the A1555G mutation.
<p>Arrows indicate no responses; Symbols, (X) left ear (O) right ear; dB HL, decibel hearing level.</p
Summary of clinical features and molecular data for nine patients carrying the A1555G mutation.
*<p>PTA, pure-tone audiometry; dB, decibels.</p
Eight Korean pedigrees presenting with nonsyndromic hearing loss were carrying the A1555G mtDNA mutation.
<p>Hearing-impaired individuals are indicated by filled symbols. Arrows denote probands. Subjects used for whole mtDNA sequence analysis are indicated by asterisks. Subjects used for the A1555G mutation screening are underlined.</p