Broadening the phenotype of DFNB28: Mutations in TRIOBP are associated with moderate, stable hereditary hearing impairment

Mieke Wesdorp, Jiddeke M. van de Kamp, Erik F. Hensen, Margit Schraders, Jaap Oostrik, Helger G. Yntema, Ilse Feenstra, Ronald J C Admiraal, Henricus P M Kunst, Mustafa Tekin, Moien Kanaan, Hannie Kremer, Ronald J E Pennings

Research output: Contribution to journalArticle

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Abstract

DFNB28 is characterized by prelingual, severe to profound sensorineural hearing impairment (HI). It is associated with mutations in exon 6 and 7 of TRIOBP and has not been reported in the European population. Here, we describe two isolated cases of Dutch origin with congenital, moderate HI and compound heterozygous mutations in TRIOBP. Three of the mutations are novel, one nonsense mutation (c.5014G>T (p.Gly1672*)) and two frameshift mutations (c.2653del (p.Arg885Alafs*120) and c.3460_3461del (p.Leu1154Alafs*29)). The fourth mutation is the known c.3232dup (p.Arg1078Profs*6) mutation. Longitudinal audiometric analyses in one of the subjects revealed that HI was stable over a period of 15 years. Vestibular function was normal. Predicted effects of the mutations do not explain the relatively mild phenotype in the presented subjects, whereas location of the mutation might well contribute to the milder HI in one of the subjects. It is known that isoform classes TRIOBP-4 and TRIOBP-5 are important for stereocilia stability and rigidity. To our knowledge, p.Gly1672* is the first pathogenic variant identified in DFNB28 that does not affect isoform class TRIOBP-4. This suggests that a single TRIOBP copy to encode wildtype TRIOBP-4 is insufficient for normal hearing, and that at least one TRIOBP copy to encode TRIOBP-5 is indispensable for normal inner ear function. Furthermore, this study demonstrates that DFNB28 can be milder than reported so far and that mutations in TRIOBP are thus associated with a heterogeneous phenotype.

Original languageEnglish (US)
JournalHearing Research
DOIs
StateAccepted/In press - May 30 2016

Fingerprint

Hearing Loss
Phenotype
Mutation
Protein Isoforms
Stereocilia
Frameshift Mutation
Autosomal Recessive 28 Deafness
Nonsense Codon
Inner Ear
Hearing
Exons
Population

Keywords

  • DFNB28
  • Genotype-phenotype correlations
  • Hereditary hearing impairment
  • TRIOBP

ASJC Scopus subject areas

  • Sensory Systems

Cite this

Wesdorp, M., van de Kamp, J. M., Hensen, E. F., Schraders, M., Oostrik, J., Yntema, H. G., ... Pennings, R. J. E. (Accepted/In press). Broadening the phenotype of DFNB28: Mutations in TRIOBP are associated with moderate, stable hereditary hearing impairment. Hearing Research. https://doi.org/10.1016/j.heares.2016.12.017

Broadening the phenotype of DFNB28 : Mutations in TRIOBP are associated with moderate, stable hereditary hearing impairment. / Wesdorp, Mieke; van de Kamp, Jiddeke M.; Hensen, Erik F.; Schraders, Margit; Oostrik, Jaap; Yntema, Helger G.; Feenstra, Ilse; Admiraal, Ronald J C; Kunst, Henricus P M; Tekin, Mustafa; Kanaan, Moien; Kremer, Hannie; Pennings, Ronald J E.

In: Hearing Research, 30.05.2016.

Research output: Contribution to journalArticle

Wesdorp, M, van de Kamp, JM, Hensen, EF, Schraders, M, Oostrik, J, Yntema, HG, Feenstra, I, Admiraal, RJC, Kunst, HPM, Tekin, M, Kanaan, M, Kremer, H & Pennings, RJE 2016, 'Broadening the phenotype of DFNB28: Mutations in TRIOBP are associated with moderate, stable hereditary hearing impairment', Hearing Research. https://doi.org/10.1016/j.heares.2016.12.017
Wesdorp, Mieke ; van de Kamp, Jiddeke M. ; Hensen, Erik F. ; Schraders, Margit ; Oostrik, Jaap ; Yntema, Helger G. ; Feenstra, Ilse ; Admiraal, Ronald J C ; Kunst, Henricus P M ; Tekin, Mustafa ; Kanaan, Moien ; Kremer, Hannie ; Pennings, Ronald J E. / Broadening the phenotype of DFNB28 : Mutations in TRIOBP are associated with moderate, stable hereditary hearing impairment. In: Hearing Research. 2016.
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abstract = "DFNB28 is characterized by prelingual, severe to profound sensorineural hearing impairment (HI). It is associated with mutations in exon 6 and 7 of TRIOBP and has not been reported in the European population. Here, we describe two isolated cases of Dutch origin with congenital, moderate HI and compound heterozygous mutations in TRIOBP. Three of the mutations are novel, one nonsense mutation (c.5014G>T (p.Gly1672*)) and two frameshift mutations (c.2653del (p.Arg885Alafs*120) and c.3460_3461del (p.Leu1154Alafs*29)). The fourth mutation is the known c.3232dup (p.Arg1078Profs*6) mutation. Longitudinal audiometric analyses in one of the subjects revealed that HI was stable over a period of 15 years. Vestibular function was normal. Predicted effects of the mutations do not explain the relatively mild phenotype in the presented subjects, whereas location of the mutation might well contribute to the milder HI in one of the subjects. It is known that isoform classes TRIOBP-4 and TRIOBP-5 are important for stereocilia stability and rigidity. To our knowledge, p.Gly1672* is the first pathogenic variant identified in DFNB28 that does not affect isoform class TRIOBP-4. This suggests that a single TRIOBP copy to encode wildtype TRIOBP-4 is insufficient for normal hearing, and that at least one TRIOBP copy to encode TRIOBP-5 is indispensable for normal inner ear function. Furthermore, this study demonstrates that DFNB28 can be milder than reported so far and that mutations in TRIOBP are thus associated with a heterogeneous phenotype.",
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AU - van de Kamp, Jiddeke M.

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AU - Oostrik, Jaap

AU - Yntema, Helger G.

AU - Feenstra, Ilse

AU - Admiraal, Ronald J C

AU - Kunst, Henricus P M

AU - Tekin, Mustafa

AU - Kanaan, Moien

AU - Kremer, Hannie

AU - Pennings, Ronald J E

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N2 - DFNB28 is characterized by prelingual, severe to profound sensorineural hearing impairment (HI). It is associated with mutations in exon 6 and 7 of TRIOBP and has not been reported in the European population. Here, we describe two isolated cases of Dutch origin with congenital, moderate HI and compound heterozygous mutations in TRIOBP. Three of the mutations are novel, one nonsense mutation (c.5014G>T (p.Gly1672*)) and two frameshift mutations (c.2653del (p.Arg885Alafs*120) and c.3460_3461del (p.Leu1154Alafs*29)). The fourth mutation is the known c.3232dup (p.Arg1078Profs*6) mutation. Longitudinal audiometric analyses in one of the subjects revealed that HI was stable over a period of 15 years. Vestibular function was normal. Predicted effects of the mutations do not explain the relatively mild phenotype in the presented subjects, whereas location of the mutation might well contribute to the milder HI in one of the subjects. It is known that isoform classes TRIOBP-4 and TRIOBP-5 are important for stereocilia stability and rigidity. To our knowledge, p.Gly1672* is the first pathogenic variant identified in DFNB28 that does not affect isoform class TRIOBP-4. This suggests that a single TRIOBP copy to encode wildtype TRIOBP-4 is insufficient for normal hearing, and that at least one TRIOBP copy to encode TRIOBP-5 is indispensable for normal inner ear function. Furthermore, this study demonstrates that DFNB28 can be milder than reported so far and that mutations in TRIOBP are thus associated with a heterogeneous phenotype.

AB - DFNB28 is characterized by prelingual, severe to profound sensorineural hearing impairment (HI). It is associated with mutations in exon 6 and 7 of TRIOBP and has not been reported in the European population. Here, we describe two isolated cases of Dutch origin with congenital, moderate HI and compound heterozygous mutations in TRIOBP. Three of the mutations are novel, one nonsense mutation (c.5014G>T (p.Gly1672*)) and two frameshift mutations (c.2653del (p.Arg885Alafs*120) and c.3460_3461del (p.Leu1154Alafs*29)). The fourth mutation is the known c.3232dup (p.Arg1078Profs*6) mutation. Longitudinal audiometric analyses in one of the subjects revealed that HI was stable over a period of 15 years. Vestibular function was normal. Predicted effects of the mutations do not explain the relatively mild phenotype in the presented subjects, whereas location of the mutation might well contribute to the milder HI in one of the subjects. It is known that isoform classes TRIOBP-4 and TRIOBP-5 are important for stereocilia stability and rigidity. To our knowledge, p.Gly1672* is the first pathogenic variant identified in DFNB28 that does not affect isoform class TRIOBP-4. This suggests that a single TRIOBP copy to encode wildtype TRIOBP-4 is insufficient for normal hearing, and that at least one TRIOBP copy to encode TRIOBP-5 is indispensable for normal inner ear function. Furthermore, this study demonstrates that DFNB28 can be milder than reported so far and that mutations in TRIOBP are thus associated with a heterogeneous phenotype.

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