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Identification and Clinical Implications of Novel MYO15A Mutations in a Non-consanguineous Korean Family by Targeted Exome Sequencing.

Chang MY, Kim AR, Kim NK, Lee C, Lee KY, Jeon WS, Koo JW, Oh SH, Park WY, Kim D, Choi BY - Mol. Cells (2015)

Bottom Line: Mutations of MYO15A are generally known to cause severe to profound hearing loss throughout all frequencies.From the literature analysis, mutations in the N-terminal domain were more frequently associated with residual hearing at low frequencies than mutations in the other regions of this gene.Therefore we suggest a hypothetical genotype-phenotype correlation whereby MYO15A mutations that affect domains other than the N-terminal domain, lead to profound SNHL throughout all frequencies and mutations that affect the N-terminal domain, result in residual hearing at low frequencies.

View Article: PubMed Central - PubMed

Affiliation: Department of Otorhinolaryngology, Seoul National University Hospital, Seoul national University College of Medicine, Seoul 110-744, Korea.

ABSTRACT
Mutations of MYO15A are generally known to cause severe to profound hearing loss throughout all frequencies. Here, we found two novel MYO15A mutations, c.3871C>T (p.L1291F) and c.5835T>G (p.Y1945X) in an affected individual carrying congenital profound sensorineural hearing loss (SNHL) through targeted resequencing of 134 known deafness genes. The variant, p.L1291F and p.Y1945X, resided in the myosin motor and IQ2 domains, respectively. The p.L1291F variant was predicted to affect the structure of the actin-binding site from three-dimensional protein modeling, thereby interfering with the correct interaction between actin and myosin. From the literature analysis, mutations in the N-terminal domain were more frequently associated with residual hearing at low frequencies than mutations in the other regions of this gene. Therefore we suggest a hypothetical genotype-phenotype correlation whereby MYO15A mutations that affect domains other than the N-terminal domain, lead to profound SNHL throughout all frequencies and mutations that affect the N-terminal domain, result in residual hearing at low frequencies. This genotype-phenotype correlation suggests that preservation of residual hearing during auditory rehabilitation like cochlear implantation should be intended for those who carry mutations in the N-terminal domain and that individuals with mutations elsewhere in MYO15A require early cochlear implantation to timely initiate speech development.

No MeSH data available.


Related in: MedlinePlus

Pathogenicity of the p.L1291F mutation. The mutation p.L1291F would alter the structure of the actin-binding site. (A) Wild type and (B) mutation show different positions of Met1793. Yellow area is the actin-binding site and red area is ATP binding site.
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f4-molce-38-9-781: Pathogenicity of the p.L1291F mutation. The mutation p.L1291F would alter the structure of the actin-binding site. (A) Wild type and (B) mutation show different positions of Met1793. Yellow area is the actin-binding site and red area is ATP binding site.

Mentions: The p.L1291F model was constructed from the wild-type structure model using FoldX by replacing p.L1291 with phenylalanine. The p.L1291F mutation was evaluated by comparing that of the wild type to the mutant model. Visual inspection of the three-dimensional structure revealed that the mutation site, although it was distant from the actin binding region (from 1972 to 1799) in terms of protein sequence, was located near the actin binding region which is crucial to the proper function of myosin (Fig. 3). In particular, mutations at this site would alter the position of the actin-binding region. As phenylalanine is larger than leucine, p.L1291F would push away the actin-binding region as a result of direct contact between p.F1291 and p.M1793 (Figs. 4A and 4B). This structural change in the actin-binding region would decrease the binding stability between actin and the myosin motor domain, which would have a detrimental effect on the interaction between actin and myosin.


Identification and Clinical Implications of Novel MYO15A Mutations in a Non-consanguineous Korean Family by Targeted Exome Sequencing.

Chang MY, Kim AR, Kim NK, Lee C, Lee KY, Jeon WS, Koo JW, Oh SH, Park WY, Kim D, Choi BY - Mol. Cells (2015)

Pathogenicity of the p.L1291F mutation. The mutation p.L1291F would alter the structure of the actin-binding site. (A) Wild type and (B) mutation show different positions of Met1793. Yellow area is the actin-binding site and red area is ATP binding site.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4588721&req=5

f4-molce-38-9-781: Pathogenicity of the p.L1291F mutation. The mutation p.L1291F would alter the structure of the actin-binding site. (A) Wild type and (B) mutation show different positions of Met1793. Yellow area is the actin-binding site and red area is ATP binding site.
Mentions: The p.L1291F model was constructed from the wild-type structure model using FoldX by replacing p.L1291 with phenylalanine. The p.L1291F mutation was evaluated by comparing that of the wild type to the mutant model. Visual inspection of the three-dimensional structure revealed that the mutation site, although it was distant from the actin binding region (from 1972 to 1799) in terms of protein sequence, was located near the actin binding region which is crucial to the proper function of myosin (Fig. 3). In particular, mutations at this site would alter the position of the actin-binding region. As phenylalanine is larger than leucine, p.L1291F would push away the actin-binding region as a result of direct contact between p.F1291 and p.M1793 (Figs. 4A and 4B). This structural change in the actin-binding region would decrease the binding stability between actin and the myosin motor domain, which would have a detrimental effect on the interaction between actin and myosin.

Bottom Line: Mutations of MYO15A are generally known to cause severe to profound hearing loss throughout all frequencies.From the literature analysis, mutations in the N-terminal domain were more frequently associated with residual hearing at low frequencies than mutations in the other regions of this gene.Therefore we suggest a hypothetical genotype-phenotype correlation whereby MYO15A mutations that affect domains other than the N-terminal domain, lead to profound SNHL throughout all frequencies and mutations that affect the N-terminal domain, result in residual hearing at low frequencies.

View Article: PubMed Central - PubMed

Affiliation: Department of Otorhinolaryngology, Seoul National University Hospital, Seoul national University College of Medicine, Seoul 110-744, Korea.

ABSTRACT
Mutations of MYO15A are generally known to cause severe to profound hearing loss throughout all frequencies. Here, we found two novel MYO15A mutations, c.3871C>T (p.L1291F) and c.5835T>G (p.Y1945X) in an affected individual carrying congenital profound sensorineural hearing loss (SNHL) through targeted resequencing of 134 known deafness genes. The variant, p.L1291F and p.Y1945X, resided in the myosin motor and IQ2 domains, respectively. The p.L1291F variant was predicted to affect the structure of the actin-binding site from three-dimensional protein modeling, thereby interfering with the correct interaction between actin and myosin. From the literature analysis, mutations in the N-terminal domain were more frequently associated with residual hearing at low frequencies than mutations in the other regions of this gene. Therefore we suggest a hypothetical genotype-phenotype correlation whereby MYO15A mutations that affect domains other than the N-terminal domain, lead to profound SNHL throughout all frequencies and mutations that affect the N-terminal domain, result in residual hearing at low frequencies. This genotype-phenotype correlation suggests that preservation of residual hearing during auditory rehabilitation like cochlear implantation should be intended for those who carry mutations in the N-terminal domain and that individuals with mutations elsewhere in MYO15A require early cochlear implantation to timely initiate speech development.

No MeSH data available.


Related in: MedlinePlus