Novel neuro-audiological findings and further evidence for TWNK involvement in Perrault syndrome

Journal of Translational Medicine

Research

Mariusz Furmanek¹  Tomasz Wolak¹  Krzysztof Kochanek²  Dominika Oziębło³  Iwona Stępniak³  Urszula Lechowicz³  Monika Ołdak³  Agnieszka Pollak³  Rafał Płoski⁴  Grażyna Tacikowska⁵  Dariusz Plewczynski⁶  Michal Lazniewski⁶  Henryk Skarżyński⁷ 

[1] Bioimaging Research Center, Institute of Physiology and Pathology of Hearing, Kajetany/Warsaw, Poland;Department of Experimental Audiology, Institute of Physiology and Pathology of Hearing, Kajetany/Warsaw, Poland;Department of Genetics, World Hearing Center, Institute of Physiology and Pathology of Hearing, Mokra 17, Kajetany/Warsaw, 05-830, Nadarzyn, Poland;Department of Medical Genetics, Medical University of Warsaw, Warsaw, Poland;Department of Otoneurology, Institute of Physiology and Pathology of Hearing, Kajetany/Warsaw, Poland;Laboratory of Functional and Structural Genomics, Centre of New Technologies, University of Warsaw, Warsaw, Poland;Oto-Rhino-Laryngology Surgery Clinic, Institute of Physiology and Pathology of Hearing, Kajetany/Warsaw, Poland;

关键词: Perrault syndrome;    TWNK;    C10orf2;    Whole exome sequencing;    Auditory neuropathy;    Hearing;    Vestibulocochlear nerve;   

DOI  :  10.1186/s12967-017-1129-4

 received in 2016-10-28, accepted in 2017-01-25,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundHearing loss and ovarian dysfunction are key features of Perrault syndrome (PRLTS) but the clinical and pathophysiological features of hearing impairment in PRLTS individuals have not been addressed. Mutations in one of five different genes HSD17B4, HARS2, LARS2, CLPP or TWNK (previous symbol C10orf2) cause the autosomal recessive disorder but they are found only in about half of the patients.MethodsWe report on two siblings with a clinical picture resembling a severe, neurological type of PRLTS. For an exhaustive characterisation of the phenotype neuroimaging with volumetric measurements and objective measures of cochlear hair cell and auditory nerve function (otoacustic emissions and auditory brainstem responses) were used. Whole exome sequencing was applied to identify the genetic cause of the disorder. Co-segregation of the detected mutations with the phenotype was confirmed by Sanger sequencing. In silico analysis including 3D protein structure modelling was used to predict the deleterious effects of the detected variants on protein function.ResultsWe found two rare biallelic mutations in TWNK, encoding Twinkle, an essential mitochondrial helicase. Mutation c.1196A>G (p.Asn399Ser) recurred for the first time in a patient with PRLTS and the second mutation c.1802G>A (p.Arg601Gln) was novel for the disorder. In both patients neuroimaging studies showed diminished cervical enlargement of the spinal cord and for the first time in PRLTS partial atrophy of the vestibulocochlear nerves and decreased grey and increased white matter volumes of the cerebellum. Morphological changes in the auditory nerves, their desynchronized activity and partial cochlear dysfunction underlay the complex mechanism of hearing impairment in the patients.ConclusionsOur study unveils novel features on the phenotypic landscape of PRLTS and provides further evidence that the newly identified for PRLTS TWNK gene is involved in its pathogenesis.

【 授权许可】

CC BY   
© The Author(s) 2017