title: PSIP1/LEDGF: a new gene likely involved in sensorineural progressive hearing loss.
abstract: Hereditary Hearing Loss (HHL) is an extremely heterogeneous disorder. Approximately 30 out of 80 known HHL genes are associated with autosomal dominant forms. Here, we identified PSIP1/LEDGF (isoform p75) as a novel strong candidate gene involved in dominant HHL. Using exome sequencing we found a frameshift deletion (c.1554_1555del leading to p.E518Dfs*2) in an Italian pedigree affected by sensorineural mild-to-moderate HHL but also showing a variable eye phenotype (i.e. uveitis, optic neuropathy). This deletion led to a premature stop codon (p.T519X) with truncation of the last 12 amino acids. PSIP1 was recently described as a transcriptional co-activator regulated by miR-135b in vestibular hair cells of the mouse inner ear as well as a possible protector against photoreceptor degeneration. Here, we demonstrate that it is ubiquitously expressed in the mouse inner ear. The PSIP1 mutation is associated with a peculiar audiometric slope toward the high frequencies. These findings indicate that PSIP1 likely plays an important role in HHL.
authors.affiliation: University of Trieste-Department of Medical, Surgical and Health Sciences, Trieste, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Girotto
authors.affiliation: Harvard Medical School-Howard Hughes Medical Institute, Department of Neurobiology, Boston MA, United States.
authors.forename: Déborah I
authors.initials: DI
authors.lastname: Scheffer
authors.affiliation: University of Trieste-Department of Medical, Surgical and Health Sciences, Trieste, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Morgan
authors.affiliation: Medical genetics, IRCCS Burlo Garofolo, Trieste, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Vozzi
authors.affiliation: University of Trieste-Department of Medical, Surgical and Health Sciences, Trieste, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Rubinato
authors.affiliation: University of Trieste-Department of Medical, Surgical and Health Sciences, Trieste, Italy.
authors.forename: Mariateresa
authors.initials: M
authors.lastname: Di Stazio
authors.affiliation: Audiology and Pediatric Otorhinolaryngology, IRCCS Burlo Garofolo, Trieste, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Muzzi
authors.affiliation: Department of Ophthalmology, IRCCS Burlo Garofolo, Trieste, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Pensiero
authors.affiliation: Harvard Medical School and Brigham and Women's Hospital, Department of Pathology, Boston MA, United States.
authors.forename: Anne B
authors.initials: AB
authors.lastname: Giersch
authors.affiliation: Harvard Medical School-Howard Hughes Medical Institute, Department of Neurobiology, Boston MA, United States.
authors.forename: David P
authors.initials: DP
authors.lastname: Corey
authors.affiliation: University of Trieste-Department of Medical, Surgical and Health Sciences, Trieste, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Gasparini
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D004252:DNA Mutational Analysis; D007758:Ear, Inner; D059472:Exome / Q000235:genetics; D005190:Family; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006319:Hearing Loss, Sensorineural / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D020871:RNA Stability / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017423:Sequence Analysis, RNA; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C504649:PSIP1 protein, human; C504650:Psip1 protein, mouse; D012333:RNA, Messenger; D014157:Transcription Factors