Limits...
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

Pedigree, auditory steady state response (ASSR) and segregation of the c.3871C>T and c.5835T>G variants of MYO15A in family SB156. (A) Targeted sequencing was performed for one affected individual (red diamond). An additional two affected individuals (circles) were recruited for Sanger validation and further analyses. (B) The ASSR test revealed that the average hearing threshold of SB156-272 was 100 dB at 4 and 10 months of age. (C) Sanger sequencing traces for the c.3871C>T (p.L1291F) + c.5835T>G (p.Y1945*) compound heterozygote (SB156-272). (D) Sanger sequencing traces for the c.5835T>G carrier (SB156-327). (E) Sanger sequencing traces for the c.3871C>T carrier (SB156-328). (F) Conservation of mutant residues among orthologs from several species; p.L1291 is conserved among all species, ranging from humans to zebrafish. (G) The sequence variants c.3871C>T and c.5835T>G reside in exon 6 (motor domain) and exon 24 (IQ2 domain) of MYO15A, respectively (adapted from Nal et al., 2007).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4588721&req=5

f1-molce-38-9-781: Pedigree, auditory steady state response (ASSR) and segregation of the c.3871C>T and c.5835T>G variants of MYO15A in family SB156. (A) Targeted sequencing was performed for one affected individual (red diamond). An additional two affected individuals (circles) were recruited for Sanger validation and further analyses. (B) The ASSR test revealed that the average hearing threshold of SB156-272 was 100 dB at 4 and 10 months of age. (C) Sanger sequencing traces for the c.3871C>T (p.L1291F) + c.5835T>G (p.Y1945*) compound heterozygote (SB156-272). (D) Sanger sequencing traces for the c.5835T>G carrier (SB156-327). (E) Sanger sequencing traces for the c.3871C>T carrier (SB156-328). (F) Conservation of mutant residues among orthologs from several species; p.L1291 is conserved among all species, ranging from humans to zebrafish. (G) The sequence variants c.3871C>T and c.5835T>G reside in exon 6 (motor domain) and exon 24 (IQ2 domain) of MYO15A, respectively (adapted from Nal et al., 2007).

Mentions: All procedures in this study were approved by the Institutional Review Boards at Seoul National University Hospital (IRBY-H-0905-041-281) and Seoul National University Bundang Hospital (IRB-B-1007-105-402). Written informed consent was obtained from all individuals (or guardians, in the case of children). One family (SB156), which showed profound SNHL in an autosomal recessive fashion, was included in this study. The family (SB156) comprised 12 individuals, 3 of whom participated in the study. The family members (SB156-272, 327 and 328) covered two generations and were evaluated at Seoul National University Bundang Hospital (Fig. 1A). Phenotypic evaluations included medical and developmental history interviews, physical examinations, and audiometric evaluation.


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)

Pedigree, auditory steady state response (ASSR) and segregation of the c.3871C>T and c.5835T>G variants of MYO15A in family SB156. (A) Targeted sequencing was performed for one affected individual (red diamond). An additional two affected individuals (circles) were recruited for Sanger validation and further analyses. (B) The ASSR test revealed that the average hearing threshold of SB156-272 was 100 dB at 4 and 10 months of age. (C) Sanger sequencing traces for the c.3871C>T (p.L1291F) + c.5835T>G (p.Y1945*) compound heterozygote (SB156-272). (D) Sanger sequencing traces for the c.5835T>G carrier (SB156-327). (E) Sanger sequencing traces for the c.3871C>T carrier (SB156-328). (F) Conservation of mutant residues among orthologs from several species; p.L1291 is conserved among all species, ranging from humans to zebrafish. (G) The sequence variants c.3871C>T and c.5835T>G reside in exon 6 (motor domain) and exon 24 (IQ2 domain) of MYO15A, respectively (adapted from Nal et al., 2007).
© Copyright Policy
Related In: Results  -  Collection

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

f1-molce-38-9-781: Pedigree, auditory steady state response (ASSR) and segregation of the c.3871C>T and c.5835T>G variants of MYO15A in family SB156. (A) Targeted sequencing was performed for one affected individual (red diamond). An additional two affected individuals (circles) were recruited for Sanger validation and further analyses. (B) The ASSR test revealed that the average hearing threshold of SB156-272 was 100 dB at 4 and 10 months of age. (C) Sanger sequencing traces for the c.3871C>T (p.L1291F) + c.5835T>G (p.Y1945*) compound heterozygote (SB156-272). (D) Sanger sequencing traces for the c.5835T>G carrier (SB156-327). (E) Sanger sequencing traces for the c.3871C>T carrier (SB156-328). (F) Conservation of mutant residues among orthologs from several species; p.L1291 is conserved among all species, ranging from humans to zebrafish. (G) The sequence variants c.3871C>T and c.5835T>G reside in exon 6 (motor domain) and exon 24 (IQ2 domain) of MYO15A, respectively (adapted from Nal et al., 2007).
Mentions: All procedures in this study were approved by the Institutional Review Boards at Seoul National University Hospital (IRBY-H-0905-041-281) and Seoul National University Bundang Hospital (IRB-B-1007-105-402). Written informed consent was obtained from all individuals (or guardians, in the case of children). One family (SB156), which showed profound SNHL in an autosomal recessive fashion, was included in this study. The family (SB156) comprised 12 individuals, 3 of whom participated in the study. The family members (SB156-272, 327 and 328) covered two generations and were evaluated at Seoul National University Bundang Hospital (Fig. 1A). Phenotypic evaluations included medical and developmental history interviews, physical examinations, and audiometric evaluation.

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