Sandra Iossa

GJB2 Gene Mutations in Syndromic Skin Diseases with Sensorineural Hearing Loss.

The GJB2 gene is located on chromosome 13q12 and it encodes the connexin 26, a transmembrane protein involved in cell-cell attachment of almost all tissues. GJB2 mutations cause autosomal recessive (DFNB1) and sometimes dominant (DFNA3) non-syndromic sensorineural hearing loss. Moreover, it has been demonstrated that connexins are involved in regulation of growth and differentiation of epidermis and, in fact, GJB2 mutations have also been identified in syndromic disorders with hearing loss associated with various skin disease phenotypes. GJB2 mutations associated with skin disease are, in general, transmitted with a dominant inheritance pattern. Nonsyndromic deafness is caused prevalently by a loss-of-function, while literature evidences suggest for syndromic deafness a mechanism based on gain-of-function. The spectrum of skin manifestations associated with some mutations seems to have a very high phenotypic variability. Why some mutations can lead to widely varying cutaneous manifestations is poorly understood and in particular, the reason why the skin disease-deafness phenotypes differ from each other thus remains unclear. This review provides an overview of recent findings concerning pathogenesis of syndromic deafness imputable to GJB2 mutations with an emphasis on relevant clinical genotype-phenotype correlations. After describing connexin 26 fundamental characteristics, the most relevant and recent information about its known mutations involved in the syndromic forms causing hearing loss and skin problems are summarized. The possible effects of the mutations on channel expression and function are discussed.

New evidence for the correlation of the p.G130V mutation in the GJB2 gene and syndromic hearing loss with palmoplantar keratoderma

The GJB2 gene located on chromosome 13q12 and encoding the connexin 26 (Cx26) protein, a transmembrane protein involved in cell–cell attachment of almost all tissues, including the skin, causes autosomal recessive and sometimes dominant nonsyndromic sensorineural hearing loss. GJB2 mutations have also been identified in syndromic disorders exhibiting hearing loss associated with skin problems. Recently, a new mutation, p.G130V in the GJB2 gene has been reported as causative for Vohwinkel syndrome. In this case the p.G130V mutation was found in two patients (son and father) with palmoplantar keratoderma. The father also showed also skin constrictions of the 2nd and 3rd toes of the right foot. Here, we report on another family with palmoplantar keratoderma associated with a dominant form of hearing loss confirming the genotype–phenotype correlation between the mutation p.G130V and the skin abnormalities observed in syndromic disorders with hearing loss as described by [Snoeckx et al. (2005) Hum Mutat 26:60–65].

Screening for GJB2 and GJB6 gene mutations in patients from Campania region with sensorineural hearing loss

Abstract The aim of this study was to screen 349 patients affected by sensorineural hearing loss (SNHL), mostly from the Campania region (southern Italy), for GJB2 gene mutations and for two deletions of the GJB6 gene (del GJB6 -D13S1830 and del GJB6 -D13S1854). We identified pathogenetic GJB2 mutations in 51 cases (15% of patients). No GJB6 mutation was found. We also examined the audiologic features of the patients for whom we had an etiologic diagnosis, in order to identify correlations between the severity of hearing loss and the type of mutation. Sumario El objetivo de este estudio fue evaluar 349 pacientes afecta-dos de una hipoacusia sensorineural (SNHL), sobre todo de la región de Campania (Italia del sur), buscando muta-ciones en el gen GJB2 y dos deleciones en el gen GJB6 (del GJB6-D13S1830 y del GJB6-13S1854). Identifica-mos mutaciones patogénicas en 51 pacientes (15% de los pacientes). No se encontraron mutaciones del gen GJB6. También examinamos los rasgos audiológicos de aquellos pacientes de quienes teníamos diagnóstico etiológico, para identificar correlaciones entre la severidad de la pérdida audi-tiva y el tipo de mutación.

Mutational analysis for GJB2, GJB6, and GJB3 genes in Campania within a universal neonatal hearing screening programme

Abstract Objective: To determine the incidence of GJB2 and GJB3 mutations and of two deletions upstream of the GJB6 gene in infants of the Campania region of southern Italy. Design: DNA samples from non-syndromic hearing-impaired infants enrolled in a neonatal screening programme for sensorineural hearing loss were analysed by PCR and by direct sequencing. The audiological features of infants with biallelic GJB2 mutations were also examined to identify genotype-phenotype correlations. Study sample: Molecular analyses were carried out in 129 affected and five unaffected infants. Results: A genetic etiology of hearing loss was identified in 28% of infants, including several at environmental risk of hearing loss. Neither GJB6 nor GJB3 (a gene not previously investigated in the Campania population) mutations were found. Conclusions: This study confirms the importance of universal neonatal hearing screening. The identification of a genetic cause in infants at environmental risk indicates that such infants should be included when investigating etiology. We confirm that also in our geographical area, c.35delG homozygotes tend to have severe symmetrical hearing loss, whereas hearing impairment is milder in compound heterozygotes. Sumario Objetivo: Determinar la incidencia de mutaciones GJB2 y GJB3 y de dos deleciones corriente arriba en el gen GJB6 en niñosde la región de Campania en el sur de Italia. Diseño: Se analizaron por PCR y por secuenciación directa muestras de ADN de niños con trastornos auditivos no sindrómicos incluidos en el programa de tamiz neonatal para hipoacusias sensorineurales. Los rasgos audiológicos de niños con mutaciones bi-alélicas del GJB2 también se examinaron para identificar correlaciones genotípicas y fenotípicas. Muestra del Estudio: Se realizó un análisis molecular en 129 niños afectados y en 5 no afectados. Resultados: Se identificó una etiología genética de la sordera en 28% de los infantes, incluyendo varios con riesgo ambiental de hipoacusia. No se encontraron mutaciones en el gen GJB6 o en el GJB3 (un gene no investigado previamente en la población de Campania). Conclusiones: Este estudio confirma la importancia del tamiz auditivo neonatal universal. La identificación de una causa genética en niños con un riesgo ambiental indica que tales infantes deberían incluirse cuando se investiga la etiología. Confirmamos que también en nuestra área geográfica, los homocigotos c.35delG tienden a tener hipoacusias simétricas severas, mientras que el trastorno auditivo es más leve en heterocigotos compuestos.

R75Q dominant mutation in GJB2 gene silenced by the in Cis recessive mutation c.35delG.

R75Q Dominant Mutation in GJB2 Gene Silenced by the in Cis Recessive Mutation c.35delG Sandra Iossa, Viviana Chinetti, Virginia Corvino, Elio Marciano, and Annamaria Franz e* CEINGE-Biotecnologie Avanzate, Naples, Italy Unit of Audiology, Department of Neurosciences, University of Naples ‘‘Federico II’’, Naples, Italy Institute of Genetics and Biophysics ‘‘A. Buzzati Traverso’’, C.N.R., Naples, Italy

Phenotypic and genetic characterization of a family carrying two Xq21.1-21.3 interstitial deletions associated with syndromic hearing loss

BackgroundSensorineural hearing impairment is a common pathological manifestation in patients affected by X-linked intellectual disability. A few cases of interstitial deletions at Xq21 with several different phenotypic characteristics have been described, but to date, a complete molecular characterization of the deletions harboring disease-causing genes is still missing. Thus, the aim of this study is to realize a detailed clinical and molecular analysis of a family affected by syndromic X-linked hearing loss with intellectual disability.ResultsClinical analyses revealed a very complex phenotype that included inner ear malformations, vestibular problems, choroideremia and hypotonia with a peculiar pattern of phenotypic variability. Genomic analysis revealed, for the first time, the presence of two close interstitial deletions in the Xq21.1-21.3, harboring 11 protein coding, 9 non-coding genes and 19 pseudogenes. Among these, 3 protein coding genes have already been associated with X-linked hearing loss, intellectual disability and choroideremia.ConclusionsIn this study we highlighted the presence of peculiar genotypic and phenotypic details in a family affected by syndromic X-linked hearing loss with intellectual disability. We identified two, previously unreported, Xq21.1-21.3 interstitial deletions. The two rearrangements, containing several genes, segregate with the clinical features, suggesting their role in the pathogenicity. However, not all the observed phenotypic features can be clearly associated with the known genes thus, further study is necessary to determine regions involved.

Novel compound heterozygous mutations in BCS1L gene causing Bjornstad syndrome in two siblings

Bjornstad syndrome is a rare condition characterized by pili torti and sensorineural hearing loss associated with pathological variations in BCS1L. Mutations in this gene are also associated with the more severe complex III deficiency and GRACILE syndrome. We report the first Italian patients with Bjornstad syndrome, two siblings with pili torti and sensorineural hearing loss, in whom we detected two novel compound heterozygous mutations in BCS1L. A thorough clinical evaluation did not reveal any features consistent with complex III deficiency or GRACILE syndrome.

SLC26A4 genotypes associated with enlarged vestibular aqueduct malformation in south Italian children with sensorineural hearing loss

aAnnamaria Franzè and Gabriella Esposito are co-first authors. *Corresponding authors: Elio Marciano, Area di Audiologia, Dipartimento di Neuroscienze, Scienze Riproduttive ed Odontostomatologiche,Via Sergio Pansini, Università di Napoli Federico II, Italy, Via Sergio Pansini 5, 80131 Naples, Italy, Phone: +39 081 746 3875, Fax: +39 081 746 3581, E-mail: marciano@unina.it; and Francesco Salvatore, CEINGEBiotecnologie Avanzate s.c. a r.l., Via Gaetano Salvatore 486, 80145 Napoli, Italy; IRCCS Fondazione SDN, Naples, Italy, Phone: +39 081 746 3133, Fax: +39 081 746 3650, E-mail: salvator@unina.it Annamaria Franzè: CEINGE-Biotecnologie Avanzate s.c. a r.l., Napoli, Italy; and Area di Audiologia, Dipartimento di Neuroscienze, Scienze Riproduttive ed Odontostomatologiche, Università di Napoli Federico II, Naples, Italy Gabriella Esposito: CEINGE-Biotecnologie Avanzate s.c. a r.l., Napoli, Italy; and Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli Federico II, Naples, Italy Carmela Di Domenico, Sandra Iossa and Giuliana Sauchelli: CEINGEBiotecnologie Avanzate s.c. a r.l., Naples, Italy Tiziana Fioretti: IRCCS Fondazione SDN, Naples, Italy Michele Cavaliere: UOC, Otorinolaringoiatria, Dipartimento di Neuroscienze, Scienze Riproduttive ed Odontostomatologiche, Università di Napoli Federico II, Naples, Italy Gennaro Auletta, Virginia Corvino, Carla Laria and Rita Malesci: Area di Audiologia, Dipartimento di Neuroscienze, Scienze Riproduttive ed Odontostomatologiche, Università di Napoli Federico II, Naples, Italy Letter to the Editor

Exclusion of TNFRSF11B as Candidate Gene for Otosclerosis in Campania Population

The etiology of otosclerosis is unknown. The etiopathogenesis of otosclerosis seems similar to that occurring in Paget’s disease of bone, for which mutations or polymorphisms in several genes have been identified. Among these, TNFRSF11B gene encoding the osteoprotegerin is produced at high levels in the normal inner ear and at low level in active otosclerotic stapes footplates. The aim of this work was to verify the presence of a correlation between the rs2073618 (N3K) polymorphism in the TNFRSF11B gene and otosclerosis. Mutational screening in the TNFRSF11B gene was performed by direct sequencing. SNPs analysis was performed by PCR and by specific restriction enzyme assay with HpaI. The significance of the association was analyzed by statistical specific software. No causative mutation has been identified but the data suggested a strong correlation between the rs2073618 (N3K) polymorphism and otosclerosis. This correlation, however, has been excluded in a case–control study. This study excluded the association between the N3K polymorphism and otosclerosis in Campania region population.