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
Department of Otorhinolaryngology, Hearing & Genes, Radboud University Medical Center, Nijmegen, The Netherlands; The Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
Hear Res. 2017 Apr;347:56-62. doi: 10.1016/j.heares.2016.12.017. Epub 2017 Jan 12.
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.Arg885Alafs120) and c.3460_3461del (p.Leu1154Alafs29)). The fourth mutation is the known c.3232dup (p.Arg1078Profs6) 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.
DFNB28的特征是语前严重至极重度感音神经性听力损失（HI）。它与TRIOBP基因第6和7外显子的突变相关，在欧洲人群中尚未有报道。在此，我们描述了两例源自荷兰的散发病例，患有先天性中度HI且TRIOBP基因存在复合杂合突变。其中三个突变是新发现的，一个无义突变（c.5014G>T (p.Gly1672*)）和两个移码突变（c.2653del (p.Arg885Alafs120) 以及c.3460_3461del (p.Leu1154Alafs29)）。第四个突变是已知的c.3232dup (p.Arg1078Profs6) 突变。对其中一名受试者的纵向听力分析显示，HI在15年期间保持稳定。前庭功能正常。突变的预测效应无法解释所呈现受试者相对较轻的表型，而突变的位置很可能导致了其中一名受试者的HI较轻。已知TRIOBP-4和TRIOBP-5亚型对静纤毛的稳定性和刚性很重要。据我们所知，p.Gly1672是在DFNB28中鉴定出的首个不影响TRIOBP-4亚型的致病变异。这表明单个编码野生型TRIOBP-4的TRIOBP拷贝不足以实现正常听力，并且至少一个编码TRIOBP-5的TRIOBP拷贝对于正常内耳功能是不可或缺的。此外，本研究表明DFNB28可能比迄今报道的情况更为轻微，因此TRIOBP基因的突变与异质性表型相关。
