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Evaluation of the contribution of the EYA4 and GRHL2 genes in Korean patients with autosomal dominant non-syndromic hearing loss.

Kim YR, Kim MA, Sagong B, Bae SH, Lee HJ, Kim HJ, Choi JY, Lee KY, Kim UK - PLoS ONE (2015)

Bottom Line: 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 conclusion, our data provide fundamental information to predict the genotypes of Korean patients diagnosed with autosomal dominant NSHL.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea; School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, Republic of Korea.

ABSTRACT
EYA4 and GRHL2 encode transcription factors that play an important role in regulating many developmental stages. Since EYA4 and GRHL2 were identified as the transcription factors for the DFNA10 and DFNA28, 8 EYA4 mutations and 2 GRHL2 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 EYA4 and GRHL2 in 87 unrelated Korean patients with autosomal dominant non-syndromic hearing loss (NSHL). A total of 4 genetic variants in the EYA4 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 GRHL2, a total of 4 genetic variants were identified, but none were associated with hearing loss in Korean patients. This suggests that GRHL2 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.

No MeSH data available.


Related in: MedlinePlus

Mutation analysis of the EYA4 gene in the YS-151 family.(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 EYA4 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 EYA4 gene including the HR domain in vertebrate species. The arrow marks the position of the p.Q393X mutation.
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pone.0119443.g001: Mutation analysis of the EYA4 gene in the YS-151 family.(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 EYA4 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 EYA4 gene including the HR domain in vertebrate species. The arrow marks the position of the p.Q393X mutation.

Mentions: The genetic analysis of the EYA4 gene identified a total of 4 sequence variants, including 2 nonsense mutations. A novel mutation, namely the single nucleotide substitution of a thymine to a cytosine at nucleotide position 1177 (c.1177C>T) in exon 13 was detected in the YS-151 family (Fig. 1A). This substitution resulted in a change in the codon at amino acid position 393 from a glutamine to a stop codon (p.Q393X), producing a truncated protein lacking the Eya VR domain (S1 Fig.). The affected family member (III-2) was heterozygous for this mutation (Fig. 1B). The PTA showed that the patient (III-2) suffered from moderate, bilateral hearing loss in low- and mid-frequencies and had increasing thresholds to profound hearing loss in the higher frequencies (Fig. 1A). A comparison of the amino acid sequence at the Eya HR domain showed that the partial region of EYA4 was highly conserved across multiple vertebrate species (Fig. 1C). This mutation was absent in all 100 normal controls, and none of the healthy controls in the 1000 Genomes Project carried this mutation. This evidence supports the hypothesis that it is a pathogenic mutation and causes hearing loss, rather than a rare polymorphism.


Evaluation of the contribution of the EYA4 and GRHL2 genes in Korean patients with autosomal dominant non-syndromic hearing loss.

Kim YR, Kim MA, Sagong B, Bae SH, Lee HJ, Kim HJ, Choi JY, Lee KY, Kim UK - PLoS ONE (2015)

Mutation analysis of the EYA4 gene in the YS-151 family.(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 EYA4 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 EYA4 gene including the HR domain in vertebrate species. The arrow marks the position of the p.Q393X mutation.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4363478&req=5

pone.0119443.g001: Mutation analysis of the EYA4 gene in the YS-151 family.(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 EYA4 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 EYA4 gene including the HR domain in vertebrate species. The arrow marks the position of the p.Q393X mutation.
Mentions: The genetic analysis of the EYA4 gene identified a total of 4 sequence variants, including 2 nonsense mutations. A novel mutation, namely the single nucleotide substitution of a thymine to a cytosine at nucleotide position 1177 (c.1177C>T) in exon 13 was detected in the YS-151 family (Fig. 1A). This substitution resulted in a change in the codon at amino acid position 393 from a glutamine to a stop codon (p.Q393X), producing a truncated protein lacking the Eya VR domain (S1 Fig.). The affected family member (III-2) was heterozygous for this mutation (Fig. 1B). The PTA showed that the patient (III-2) suffered from moderate, bilateral hearing loss in low- and mid-frequencies and had increasing thresholds to profound hearing loss in the higher frequencies (Fig. 1A). A comparison of the amino acid sequence at the Eya HR domain showed that the partial region of EYA4 was highly conserved across multiple vertebrate species (Fig. 1C). This mutation was absent in all 100 normal controls, and none of the healthy controls in the 1000 Genomes Project carried this mutation. This evidence supports the hypothesis that it is a pathogenic mutation and causes hearing loss, rather than a rare polymorphism.

Bottom Line: 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 conclusion, our data provide fundamental information to predict the genotypes of Korean patients diagnosed with autosomal dominant NSHL.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea; School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, Republic of Korea.

ABSTRACT
EYA4 and GRHL2 encode transcription factors that play an important role in regulating many developmental stages. Since EYA4 and GRHL2 were identified as the transcription factors for the DFNA10 and DFNA28, 8 EYA4 mutations and 2 GRHL2 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 EYA4 and GRHL2 in 87 unrelated Korean patients with autosomal dominant non-syndromic hearing loss (NSHL). A total of 4 genetic variants in the EYA4 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 GRHL2, a total of 4 genetic variants were identified, but none were associated with hearing loss in Korean patients. This suggests that GRHL2 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.

No MeSH data available.


Related in: MedlinePlus