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



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.



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.



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.
Department of Genetics, World Hearing Center, Institute of Physiology and Pathology of Hearing, Mokra 17, Kajetany/Warsaw, 05-830, Nadarzyn, Poland. m.oldak@ifps.org.pl.
Monika
M
Ołdak
Department of Genetics, World Hearing Center, Institute of Physiology and Pathology of Hearing, Mokra 17, Kajetany/Warsaw, 05-830, Nadarzyn, Poland.
Dominika
D
Oziębło
Department of Genetics, World Hearing Center, Institute of Physiology and Pathology of Hearing, Mokra 17, Kajetany/Warsaw, 05-830, Nadarzyn, Poland.
Agnieszka
A
Pollak
Department of Genetics, World Hearing Center, Institute of Physiology and Pathology of Hearing, Mokra 17, Kajetany/Warsaw, 05-830, Nadarzyn, Poland.
Iwona
I
Stępniak
Laboratory of Functional and Structural Genomics, Centre of New Technologies, University of Warsaw, Warsaw, Poland.
Michal
M
Lazniewski
Department of Genetics, World Hearing Center, Institute of Physiology and Pathology of Hearing, Mokra 17, Kajetany/Warsaw, 05-830, Nadarzyn, Poland.
Urszula
U
Lechowicz
Department of Experimental Audiology, Institute of Physiology and Pathology of Hearing, Kajetany/Warsaw, Poland.
Krzysztof
K
Kochanek
Bioimaging Research Center, Institute of Physiology and Pathology of Hearing, Kajetany/Warsaw, Poland.
Mariusz
M
Furmanek
Department of Otoneurology, Institute of Physiology and Pathology of Hearing, Kajetany/Warsaw, Poland.
Grażyna
G
Tacikowska
Laboratory of Functional and Structural Genomics, Centre of New Technologies, University of Warsaw, Warsaw, Poland.
Dariusz
D
Plewczynski
Bioimaging Research Center, Institute of Physiology and Pathology of Hearing, Kajetany/Warsaw, Poland.
Tomasz
T
Wolak
Department of Medical Genetics, Medical University of Warsaw, Warsaw, Poland.
Rafał
R
Płoski
Oto-Rhino-Laryngology Surgery Clinic, Institute of Physiology and Pathology of Hearing, Kajetany/Warsaw, Poland.
Henryk
H
Skarżyński
D000328:Adult; D000595:Amino Acid Sequence; D001301:Audiometry, Pure-Tone; D002648:Child; D002675:Child, Preschool; D004265:DNA Helicases / Q000737:chemistry / Q000235:genetics*; D003710:Demography; D005260:Female; D023961:Gonadal Dysgenesis, 46,XX / Q000235:genetics*; D006319:Hearing Loss, Sensorineural / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D009420:Nervous System / Q000473:pathology*; D010375:Pedigree; D016415:Sequence Alignment; D055815:Young Adult
D024101:Mitochondrial Proteins; D004265:DNA Helicases; C431576:TWNK protein, human
Auditory neuropathy; C10orf2; Hearing; Perrault syndrome; TWNK; Vestibulocochlear nerve; Whole exome sequencing