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.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
El síndrome de Marfan es una enfermedad pleitrópica del tejido conjuntivo que exhibe un patrón de herencia autosómico dominante, en su mayoría causado por mutaciones en el gen FBN1, que se encuentra ...en el cromosoma 15q21.1 y codifica a la fibrilina 1. Se presenta un caso de síndrome de Marfan que cursa con manifestación sistémica severa cardíaca y principlamente ocular. El paciente presentó una valoración multidisciplinaria y su diagnóstico clínico fue asociado con la mutación c.3037G>A en el gen FBN1. La identificación de esta alteración genética debe promover una pronta evaluación y supervisión con el fin de evitar las desvastadoras consecuencias, tales como el fenotipo cardíaco y ocular. El modelado comparativo de proteínas resalta la importancia de la conservación de la estructura del dominio de la fibrilina-1 dependiente de calcio similar al factor de crecimiento epidérmico y por lo tanto el proceso de formación microfibrilar. Este informe tiene como objetivo resaltar la importancia de un diagnóstico clínico y molecular temprano y el enfoque multidisciplinariode esta entidad genética. Palabras clave: síndrome de Marfan; c.3037G>A; FBN1; manifestaciones oculares. Marfan syndrome is a pleiotropic connective tissue disease inherited as an autosomal dominant trait, mostly caused by mutations in the FBN1 gene, which is located on chromosome 15q21.1 and encoding fibrillin 1. We report a case of Marfan syndrome presenting with severe ocular and systemic manifestations, such as cardiac congenital anomalies. The patient underwent a multidisciplinary approach and his clinical diagnosis was associated with a c.3037G>A mutation in the FBN1 gene. Identification of this genetic alteration should instigate a prompt multidisciplinary assessment and monitoring, in order to prevent devastating consequences such as cardiac and ocular phenotype. Molecular modeling of the mutation highlighted the importance of the preservation of the calcium-dependent structure of an epidermal-growth-factor-like domain of fibrillin-1 and consequently the microfibrillar formation process. This report aims to highlight the importance of an early clinical and molecular diagnosis and once more, the importance of the multidisciplinary approach of this genetic entity. Keywords: Marfan syndrome; c.3037G>A; FBN1; phenotype.
Marfan syndrome is a pleiotropic connective tissue disease inherited as an
autosomal dominant trait, mostly caused by mutations in the FBN1 gene, which is located on
chromosome 15q21.1 and encoding ...fibrillin 1. We report a case of Marfan syndrome presenting
with severe ocular and systemic manifestations, such as cardiac congenital anomalies.
The patient underwent a multidisciplinary approach and his clinical diagnosis was associated
with a c.3037G>A mutation in the FBN1 gene. Identification of this genetic alteration should
instigate a prompt multidisciplinary assessment and monitoring, in order to prevent devastating
consequences such as cardiac and ocular phenotype. Molecular modeling of the mutation
highlighted the importance of the preservation of the calcium-dependent structure of an epidermal-
growth-factor-like domain of fibrillin-1 and consequently the microfibrillar formation
process. This report aims to highlight the importance of an early clinical and molecular diagnosis
and once more, the importance of the multidisciplinary approach of this genetic entity.
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