Novel neuro-audiological findings and further evidence for TWNK involvement in Perrault syndrome - PubMed (original) (raw)

doi: 10.1186/s12967-017-1129-4.

Dominika Oziębło 2, Agnieszka Pollak 2, Iwona Stępniak 2, Michal Lazniewski 3, Urszula Lechowicz 2, Krzysztof Kochanek 4, Mariusz Furmanek 5, Grażyna Tacikowska 6, Dariusz Plewczynski 3, Tomasz Wolak 5, Rafał Płoski 7, Henryk Skarżyński 8

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

Monika Ołdak et al. J Transl Med. 2017.

Abstract

Background: Hearing 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.

Methods: We 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.

Results: We 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.

Conclusions: Our 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.

Keywords: Auditory neuropathy; C10orf2; Hearing; Perrault syndrome; TWNK; Vestibulocochlear nerve; Whole exome sequencing.

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Figures

Fig. 1

Fig. 1

Brain and spine MRI in the proband. The left column shows sagittal T2 weighted images of the head and cervical spine (a proband, b control) with the measurements of spinal cord thickness at different levels. The middle column shows cross-section of the spinal cord (c proband, d control). The right column shows transverse heavy T2 weighted images of sub-millimeter slice thickness displaying the cochlear nerve, pointed with a red arrow (e proband, f control)

Fig. 2

Fig. 2

Pure tone audiometry (a) and ABRs (b) of the proband. a “O” and “X” symbols denote air conduction thresholds in the right and left ear, respectively and “Δ” denotes masked air conduction at high frequencies in the right ear; “[” or “]” denote masked bone conduction. b Shown are ABR recordings after click stimulus at an acoustic level of 90 dB normal hearing level (nHL) and presentation rate of 11/s

Fig. 3

Fig. 3

Identification of TWNK mutations in the analyzed families. a Pedigree of the investigated family. The proband is marked with an arrow. Black symbols indicate individuals affected with PRLTS5 and open symbols indicate unaffected individuals; diagonal line denotes the deceased father. The TWNK genotypes identified in the family members are reported at the cDNA and protein levels according to the HGVS-nomenclature (

http://varnomen.hgvs.org/

; accessed 07/2016). b WES in the proband revealed an A>G transition (upper left panel) and G>A transition (lower left panel), corresponding to p.Asn399Ser (AAT>AGT) and p.Arg601Gln (CGG>CAG), respectively, in the TWNK gene. Direct Sanger sequencing of TWNK confirmed the presence of the two mutations (right panel). For each mutation sequencing of the forward (top) and the reverse (bottom) strand is shown

Fig. 4

Fig. 4

Multiple protein sequence alignment and 3D structure of the human Twinkle protein in regions encompassing p.Asn399Ser and p.Arg601Gln mutations. a Multiple protein sequence alignment of selected sequences. Two regions of the twinkle protein are shown: (i) the region joining the linker and the helicase domains (Region I) and (ii) the region involved in stabilizing the adenine ring of ATP (Regions II and III). The numbers above the alignment correspond to the amino acid position in the human protein sequence. (b–c) Two interacting monomers of the Twinkle protein are colored white and blue. Changes in the conformation of a region next to the linker domain in p.Asn399Ser mutant (b) and in wild type (c) proteins are shown. (d–e) Changes in hydrogen bonds network resulting in weakened ATP binding in the p.Arg601Gln mutant (d) as compared to wild type (e) protein are depicted

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