TY - JOUR T1 - Next-generation sequencing identified SPATC1L as a possible candidate gene for both early-onset and age-related hearing loss. JF - Eur J Hum Genet Y1 - 2019 A1 - Morgan, Anna A1 - Vuckovic, Dragana A1 - Krishnamoorthy, Navaneethakrishnan A1 - Rubinato, Elisa A1 - Ambrosetti, Umberto A1 - Castorina, Pierangela A1 - Franzè, Annamaria A1 - Vozzi, Diego A1 - La Bianca, Martina A1 - Cappellani, Stefania A1 - Di Stazio, Mariateresa A1 - Gasparini, Paolo A1 - Girotto, Giorgia AB -

Hereditary hearing loss (HHL) and age-related hearing loss (ARHL) are two major sensory diseases affecting millions of people worldwide. Despite many efforts, additional HHL-genes and ARHL genetic risk factors still need to be identified. To fill this gap a large genomic screening based on next-generation sequencing technologies was performed. Whole exome sequencing in a 3-generation Italian HHL family and targeted re-sequencing in 464 ARHL patients were performed. We detected three variants in SPATC1L: a nonsense allele in an HHL family and a frameshift insertion and a missense variation in two unrelated ARHL patients. In silico molecular modelling of all variants suggested a significant impact on the structural stability of the protein itself, likely leading to deleterious effects and resulting in truncated isoforms. After demonstrating Spatc1l expression in mice inner ear, in vitro functional experiments were performed confirming the results of the molecular modelling studies. Finally, a candidate-gene population-based statistical study in cohorts from Caucasus and Central Asia revealed a statistically significant association of SPATC1L with normal hearing function at low and medium hearing frequencies. Overall, the amount of different genetic data presented here (variants with early-onset and late-onset hearing loss in addition to genetic association with normal hearing function), together with relevant functional evidence, likely suggest a role of SPATC1L in hearing function and loss.

VL - 27 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/30177775?dopt=Abstract ER - TY - JOUR T1 - PSIP1/LEDGF: a new gene likely involved in sensorineural progressive hearing loss. JF - Sci Rep Y1 - 2015 A1 - Girotto, Giorgia A1 - Scheffer, Deborah I A1 - Morgan, Anna A1 - Vozzi, Diego A1 - Rubinato, Elisa A1 - Di Stazio, Mariateresa A1 - Muzzi, Enrico A1 - Pensiero, Stefano A1 - Giersch, Anne B A1 - Corey, David P A1 - Gasparini, Paolo AB -

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.

VL - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26689366?dopt=Abstract ER - TY - JOUR T1 - A girl with photosensitivity and hepatic steatosis. JF - J Pediatr Y1 - 2014 A1 - Pavan, Matteo A1 - Gortani, Giulia A1 - Rubinato, Elisa A1 - Faletra, Flavio A1 - Pastore, Serena A1 - Ventura, Alessandro KW - Child KW - Diagnosis, Differential KW - Fatty Liver KW - Female KW - Humans KW - Photosensitivity Disorders KW - Protoporphyria, Erythropoietic VL - 165 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24704299?dopt=Abstract ER - TY - JOUR T1 - A novel deletion mutation involving TMEM38B in a patient with autosomal recessive osteogenesis imperfecta. JF - Gene Y1 - 2014 A1 - Rubinato, Elisa A1 - Morgan, Anna A1 - D'Eustacchio, Angela A1 - Pecile, Vanna A1 - Gortani, Giulia A1 - Gasparini, Paolo A1 - Faletra, Flavio KW - Child KW - Chromosomes, Human, Pair 19 KW - DNA Mutational Analysis KW - Exons KW - Female KW - Genes, Recessive KW - Homozygote KW - Humans KW - Ion Channels KW - Osteogenesis Imperfecta KW - Sequence Deletion AB -

Osteogenesis imperfecta (OI) is a hereditary bone disease characterized by decreased bone density and multiple fractures, usually inherited in an autosomal dominant manner. Several gene encoding proteins related to collagen metabolism have been described in some cases of autosomal recessive OI (including CRTAP, LEPRE1, PPIB, FKBP65, SERPINF1, BMP1, WNT1, FKBP10). Recently, TMEM38B, a gene that encodes TRIC-B, a monovalent cation-specific channel involved in calcium flux from intracellular stores and in cell differentiation, has been associated with autosomal recessive OI. Here, we describe the second deletion-mutation involving the TMEM38B gene in an 11 year-old Albanian female with a clinical phenotype of OI, born to parents with suspected consanguinity. SNP array analysis revealed a homozygous region larger than 2 Mb that overlapped with the TMEM38B locus and was characterized by a 35 kb homozygous deletion involving exons 1 and 2 of TMEM38B gene.

VL - 545 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24835313?dopt=Abstract ER -