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Hearing Disorders: HELP
Articles by Pierangela Castorina
Based on 9 articles published since 2010
(Why 9 articles?)
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Between 2010 and 2020, P. Castorina wrote the following 9 articles about Hearing Disorders.
 
+ Citations + Abstracts
1 Article Next-generation sequencing identified SPATC1L as a possible candidate gene for both early-onset and age-related hearing loss. 2019

Morgan, Anna / Vuckovic, Dragana / Krishnamoorthy, Navaneethakrishnan / Rubinato, Elisa / Ambrosetti, Umberto / Castorina, Pierangela / Franzè, Annamaria / Vozzi, Diego / La Bianca, Martina / Cappellani, Stefania / Di Stazio, Mariateresa / Gasparini, Paolo / Girotto, Giorgia. ·Department of Medical Sciences, University of Trieste, Trieste, Italy. anna.morgan@burlo.trieste.it. · Department of Medical Sciences, University of Trieste, Trieste, Italy. · Sidra Medical and Research Center, Doha, Qatar. · Heart Science Centre, National Heart and Lung Institute, Imperial College London, London, UK. · UO Audiology, Fondazione IRCCS Ca Granda, Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milan, Italy. · Audiology Unit, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy. · Ceinge Biotecnologie Avanzate, Naples, Italy; Istituto di Audiologia, Dipartimento di Neuroscienze, Scienze Riproduttive e Odontostomatologiche, Università di Napoli "Federico II", Naples, Italy. · Medical Genetics, Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", Trieste, Italy. ·Eur J Hum Genet · Pubmed #30177775.

ABSTRACT: 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.

2 Article First independent replication of the involvement of LARS2 in Perrault syndrome by whole-exome sequencing of an Italian family. 2016

Soldà, Giulia / Caccia, Sonia / Robusto, Michela / Chiereghin, Chiara / Castorina, Pierangela / Ambrosetti, Umberto / Duga, Stefano / Asselta, Rosanna. ·Department of Biomedical Sciences, Humanitas University, Milan, Italy. · Humanitas Clinical and Research Center, Milan, Italy. · Department of Biomedical and Clinical Sciences "Luigi Sacco", Università degli Studi di Milano - LITA Vialba, Milan, Italy. · UO Audiologia, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy. · Dipartimento di Scienze Cliniche e di Comunità, Università degli Studi di Milano, Milan, Italy. ·J Hum Genet · Pubmed #26657938.

ABSTRACT: Perrault syndrome (MIM #233400) is a rare autosomal recessive disorder characterized by ovarian dysgenesis and primary ovarian insufficiency in females, and progressive hearing loss in both genders. Recently, mutations in five genes (HSD17B4, HARS2, CLPP, LARS2 and C10ORF2) were found to be responsible for Perrault syndrome, although they do not account for all cases of this genetically heterogeneous condition. We used whole-exome sequencing to identify pathogenic variants responsible for Perrault syndrome in an Italian pedigree with two affected siblings. Both patients were compound heterozygous for two novel missense variants within the mitochondrial leucyl-tRNA synthetase (LARS2): NM_015340.3:c.899C>T(p.Thr300Met) and c.1912G>A(p.Glu638Lys). Both variants cosegregated with the phenotype in the family. p.Thr300 and p.Glu638 are evolutionarily conserved residues, and are located, respectively, within the editing domain and immediately before the catalytically important KMSKS motif. Homology modeling using as template the E. coli leucyl-tRNA synthetase provided further insights on the possible pathogenic effects of the identified variants. This represents the first independent replication of the involvement of LARS2 mutations in Perrault syndrome, contributing valuable information for the further understanding of this disease.

3 Article Usher syndrome: an effective sequencing approach to establish a genetic and clinical diagnosis. 2015

Lenarduzzi, S / Vozzi, D / Morgan, A / Rubinato, E / D'Eustacchio, A / Osland, T M / Rossi, C / Graziano, C / Castorina, P / Ambrosetti, U / Morgutti, M / Girotto, G. ·Department of Medical Sciences, University of Trieste, Italy. · Institute for Maternal and Child Health-IRCCS "Burlo Garofolo", Trieste, Italy. · Department of Genetics, University of Bologna, Policlinico S. Orsola-Malpighi, Bologna, Italy. · UO Audiology, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milan, Italy. · UO Audiology, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milan, Italy; Audiology Unit, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy. · Department of Medical Sciences, University of Trieste, Italy. Electronic address: giorgia.girotto@burlo.trieste.it. ·Hear Res · Pubmed #25575603.

ABSTRACT: Usher syndrome is an autosomal recessive disorder characterized by retinitis pigmentosa, sensorineural hearing loss and, in some cases, vestibular dysfunction. The disorder is clinically and genetically heterogeneous and, to date, mutations in 11 genes have been described. This finding makes difficult to get a precise molecular diagnosis and offer patients accurate genetic counselling. To overcome this problem and to increase our knowledge of the molecular basis of Usher syndrome, we designed a targeted resequencing custom panel. In a first validation step a series of 16 Italian patients with known molecular diagnosis were analysed and 31 out of 32 alleles were detected (97% of accuracy). After this step, 31 patients without a molecular diagnosis were enrolled in the study. Three out of them with an uncertain Usher diagnosis were excluded. One causative allele was detected in 24 out 28 patients (86%) while the presence of both causative alleles characterized 19 patients out 28 (68%). Sixteen novel and 27 known alleles were found in the following genes: USH2A (50%), MYO7A (7%), CDH23 (11%), PCDH15 (7%) and USH1G (2%). Overall, on the 44 patients the protocol was able to characterize 74 alleles out of 88 (84%). These results suggest that our panel is an effective approach for the genetic diagnosis of Usher syndrome leading to: 1) an accurate molecular diagnosis, 2) better genetic counselling, 3) more precise molecular epidemiology data fundamental for future interventional plans.

4 Article The expanding spectrum of PRPS1-associated phenotypes: three novel mutations segregating with X-linked hearing loss and mild peripheral neuropathy. 2015

Robusto, Michela / Fang, Mingyan / Asselta, Rosanna / Castorina, Pierangela / Previtali, Stefano C / Caccia, Sonia / Benzoni, Elena / De Cristofaro, Raimondo / Yu, Cong / Cesarani, Antonio / Liu, Xuanzhu / Li, Wangsheng / Primignani, Paola / Ambrosetti, Umberto / Xu, Xun / Duga, Stefano / Soldà, Giulia. ·Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milan, Italy. · BGI-Shenzhen, Shenzhen, China. · Dipartimento di Scienze Cliniche e di Comunità, Università degli Studi di Milano, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, UO Audiologia, Milan, Italy. · Division of Neuroscience, Institute of Experimental Neurology, San Raffaele Scientific Institute, Milan, Italy. · Laboratory of Medical Genetics, Molecular Genetic Sector, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy. · Haemostasis Research Center, Institute of Internal Medicine and Geriatrics, Catholic University School of Medicine, Rome, Italy. ·Eur J Hum Genet · Pubmed #25182139.

ABSTRACT: Next-generation sequencing is currently the technology of choice for gene/mutation discovery in genetically-heterogeneous disorders, such as inherited sensorineural hearing loss (HL). Whole-exome sequencing of a single Italian proband affected by non-syndromic HL identified a novel missense variant within the PRPS1 gene (NM_002764.3:c.337G>T (p.A113S)) segregating with post-lingual, bilateral, progressive deafness in the proband's family. Defects in this gene, encoding the phosphoribosyl pyrophosphate synthetase 1 (PRS-I) enzyme, determine either X-linked syndromic conditions associated with hearing impairment (eg, Arts syndrome and Charcot-Marie-Tooth neuropathy type X-5) or non-syndromic HL (DFNX1). A subsequent screening of the entire PRPS1 gene in 16 unrelated probands from X-linked deaf families led to the discovery of two additional missense variants (c.343A>G (p.M115V) and c.925G>T (p.V309F)) segregating with hearing impairment, and associated with mildly-symptomatic peripheral neuropathy. All three variants result in a marked reduction (>60%) of the PRS-I activity in the patients' erythrocytes, with c.343A>G (p.M115V) and c.925G>T (p.V309F) affecting more severely the enzyme function. Our data significantly expand the current spectrum of pathogenic variants in PRPS1, confirming that they are associated with a continuum disease spectrum, thus stressing the importance of functional studies and detailed clinical investigations for genotype-phenotype correlation.

5 Article Enrichment of LOVD-USHbases with 152 USH2A genotypes defines an extensive mutational spectrum and highlights missense hotspots. 2014

Baux, David / Blanchet, Catherine / Hamel, Christian / Meunier, Isabelle / Larrieu, Lise / Faugère, Valérie / Vaché, Christel / Castorina, Pierangela / Puech, Bernard / Bonneau, Dominique / Malcolm, Sue / Claustres, Mireille / Roux, Anne-Françoise. ·CHU Montpellier, Laboratoire de Génétique Moléculaire, Montpellier, F-34000, France. ·Hum Mutat · Pubmed #24944099.

ABSTRACT: Alterations of USH2A, encoding usherin, are responsible for more than 70% of cases of Usher syndrome type II (USH2), a recessive disorder that combines moderate to severe hearing loss and retinal degeneration. The longest USH2A transcript encodes usherin isoform b, a 5,202-amino-acid transmembrane protein with an exceptionally large extracellular domain consisting notably of a Laminin N-terminal domain and numerous Laminin EGF-like (LE) and Fibronectin type III (FN3) repeats. Mutations of USH2A are scattered throughout the gene and mostly private. Annotating these variants is therefore of major importance to correctly assign pathogenicity. We have extensively genotyped a novel cohort of 152 Usher patients and identified 158 different mutations, of which 93 are newly described. Pooling this new data with the existing pathogenic variants already incorporated in USHbases reveals several previously unappreciated features of the mutational spectrum. We show that parts of the protein are more likely to tolerate single amino acid variations, whereas others constitute pathogenic missense hotspots. We have found, in repeated LE and FN3 domains, a nonequal distribution of the missense mutations that highlights some crucial positions in usherin with possible consequences for the assessment of the pathogenicity of the numerous missense variants identified in USH2A.

6 Article Emerging ciliopathies: are respiratory cilia compromised in Usher syndrome? 2014

Piatti, G / De Santi, M M / Brogi, M / Castorina, P / Ambrosetti, U. ·Department of Pathophysiology and Transplantation, University of Milan, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Italy. Electronic address: gioia.piatti@unimi.it. · Department of Human Pathology and Oncology, University of Siena, Italy. · Department of Clinical Sciences and Community, University of Milan, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Italy. ·Am J Otolaryngol · Pubmed #24602455.

ABSTRACT: PURPOSE: Usher syndrome is a ciliopathy involving photoreceptors and cochlear hair cells (sensory cilia): since sensory and motor ciliopathies can overlap, we analysed the respiratory cilia (motile) in 17 patients affected by Usher syndrome and 18 healthy control subject. PATIENTS AND METHODS: We studied the mucociliary transport time with the saccharine test, ciliary motility and ultrastructure of respiratory cilia obtained by nasal brushing; we also recorded the classical respiratory function values by spirometry. RESULTS: All enrolled subjects showed normal respiratory function values. The mean mucociliary transport time with saccharine was 22.33 ± 17.96 min, which is in the range of normal values. The mean ciliary beat frequency of all subjects was 8.81 ± 2.18 Hz, which is a value approaching the lower physiological limit. None of the classical ciliary alterations characterizing the "ciliary primary dyskinesia" was detected, although two patients showed alterations in number and arrangement of peripheral microtubules and one patient had abnormal ciliary roots. CONCLUSIONS: Respiratory cilia in Usher patients don't seem to have evident ultrastructural alterations, as expected, but the fact that the ciliary motility appeared slightly reduced could emphasize that a rigid distinction between sensory and motor ciliopathies may not reflect what really occurs.

7 Article Molecular and functional studies of 4 candidate loci in Pendred syndrome and nonsyndromic hearing loss. 2012

Cirello, Valentina / Bazzini, Claudia / Vezzoli, Valeria / Muzza, Marina / Rodighiero, Simona / Castorina, Pierangela / Maffini, Antonia / Bottà, Guido / Persani, Luca / Beck-Peccoz, Paolo / Meyer, Giuliano / Fugazzola, Laura. ·Dept. of Medical Sciences, Università degli Studi, Milan, Italy. ·Mol Cell Endocrinol · Pubmed #22285650.

ABSTRACT: Patients with PS or non-syndromic deafness were submitted to genetic/functional analyzes of SLC26A4, of its binding domain for FOXI1 (FOXI1-DBD), of the transcription activator FOXI1, and of the potassium channel KCNJ10. SLC26A4 was the most frequently mutated gene. An altered intracellular localization with immunocytochemistry, and a hampered maturation process were demonstrated for two novel SLC26A4 variants. Biochemical and immunocytochemical analyzes led to the development of a more sensitive fluorometric functional assay able to reveal the partial loss-of-function of SLC26A4 mutations. A novel missense variant was found in FOXI1 gene, though functional analysis showed no significant impairment in the transcriptional activation of SLC26A4. Finally, 3 patients were found to harbor a variant in KCNJ10, which was classified as polymorphism. The novelty of the study resides in the analysis of all the 4 candidate genetic loci linked to PS/non-syndromic deafness, and in the precise definition of the thyroid phenotype. PS was invariably associated with biallelic mutations of SLC26A4, whereas the genetic origin of non-syndromic deafness remained largely undetermined, since monoallelic SLC26A4 variants accounted for one fourth of the cases and FOXI1 and KCNJ10 were not involved in this series.

8 Article A novel mutation within the MIR96 gene causes non-syndromic inherited hearing loss in an Italian family by altering pre-miRNA processing. 2012

Soldà, Giulia / Robusto, Michela / Primignani, Paola / Castorina, Pierangela / Benzoni, Elena / Cesarani, Antonio / Ambrosetti, Umberto / Asselta, Rosanna / Duga, Stefano. ·Dipartimento di Biologia e Genetica per Scienze Mediche, Università degli Studi di Milano, Milan, Italy. giulia.solda@unimi.it ·Hum Mol Genet · Pubmed #22038834.

ABSTRACT: The miR-96, miR-182 and miR-183 microRNA (miRNA) family is essential for differentiation and function of the vertebrate inner ear. Recently, point mutations within the seed region of miR-96 were reported in two Spanish families with autosomal dominant non-syndromic sensorineural hearing loss (NSHL) and in a mouse model of NSHL. We screened 882 NSHL patients and 836 normal-hearing Italian controls and identified one putative novel mutation within the miR-96 gene in a family with autosomal dominant NSHL. Although located outside the mature miR-96 sequence, the detected variant replaces a highly conserved nucleotide within the companion miR-96*, and is predicted to reduce the stability of the pre-miRNA hairpin. To evaluate the effect of the detected mutation on miR-96/mir-96* biogenesis, we investigated the maturation of miR-96 by transient expression in mammalian cells, followed by real-time reverse-transcription polymerase chain reaction (PCR). We found that both miR-96 and miR-96* levels were significantly reduced in the mutant, whereas the precursor levels were unaffected. Moreover, miR-96 and miR-96* expression levels could be restored by a compensatory mutation that reconstitutes the secondary structure of the pre-miR-96 hairpin, demonstrating that the mutation hinders precursor processing, probably interfering with Dicer cleavage. Finally, even though the mature miR-96 sequence is not altered, we demonstrated that the identified mutation significantly impacts on miR-96 regulation of selected targets. In conclusion, we provide further evidence of the involvement of miR-96 mutations in human deafness and demonstrate that a quantitative defect of this miRNA may contribute to NSHL.

9 Article GJB2 and MTRNR1 contributions in children with hearing impairment from Northern Cameroon. 2011

Trotta, Luca / Iacona, Elisabetta / Primignani, Paola / Castorina, Pierangela / Radaelli, Chiara / Del Bo, Luca / Coviello, Domenico / Ambrosetti, Umberto. ·Laboratory of Medical Genetics, Molecular Genetic Sector, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. ·Int J Audiol · Pubmed #21114417.

ABSTRACT: OBJECTIVE: the aim of this work was to evaluate the possible different impacts of genetic and environmental factors in childhood deafness in northern Cameroon. GJB2 mutations are responsible for more than half of all cases of prelingual nonsyndromic recessive deafness in Caucasians, representing the most important deafness-causing factor in the industrialized world. Other genes such as MTRNR1 are also involved. In sub-Saharan Africa, environmental factors seem to dominate genetic contributions, but few studies on the etiology of deafness in Africa are available for comparison. DESIGN: prospective cross sectional study. STUDY SAMPLE: we performed a molecular screen of the GJB2 and MTRNR1 genes in 70 deaf children and 67 unaffected controls in Maroua (Cameroon) and a literature analysis focused on deafness epidemiology in developing countries. RESULTS: no GJB2 mutations emerged, and only a single MTRNR1 variant that may be pathogenic was found. CONCLUSION: environmental factors turn out to be more relevant than genetic factor in the Maroua population.