Human cytomegalovirus (HCMV) and hearing impairment: Infection of fibroblast cells with HCMV induces chromosome breaks at 1q23.3, between loci DFNA7 and DFNA49—Both involved in dominantly inherited, sensorineural, hearing impairment

Nystad, Mona; Fagerheim, Toril; Brox, Vigdis; Fortunato, Elizabeth A.; Nilssen, Øivind

doi:10.1016/j.mrfmmm.2007.07.009

Cited by 29 publications

(26 citation statements)

References 32 publications

(45 reference statements)

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“…Although congenital CMV infection did not induce GJB2 mutation in this study, some previous experiments in vitro indicated that CMV infection did induce genetic damage at 1q23.3, with a breakpoint situated between two hearing impairment loci, DFNA49 and DFNA7 (14). Fortunato et al (17) demonstrated that infection of S-phase human fibroblast cells with CMV resulted in chromosome breaks at positions 1q21 and 1q42; these two chromosomal band locations contain loci involved in dominantly and recessively inherited hearing impairment, respectively.…”

Section: Discussioncontrasting

confidence: 73%

“…As genetic factors, the mutations of the gap junction β-2 (GJB2) gene were considered an important cause of SNHL (9)(10)(11)(12). Studies indicate that congenital CMV infection may cause chromosome aberrations, including selective chromosome breakages, chromosome pulverization, premature chromatid condensation, and structural injury to the centrosome (13)(14)(15)(16)(17)(18), e.g., genetic damages on 1q23.3 (14), 1q21, and 1q42 (17). However, whether CMV infection can induce mutations of GJB2 on human chromosome 13q11-q12 remains unclear.…”

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confidence: 99%

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Does congenital cytomegalovirus infection lead to hearing loss by inducing mutation of the GJB2 gene?

Li¹,

Tan²,

Zhou³

et al. 2013

Pediatr Res

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Background: Congenital cytomegalovirus (CMV) infection and mutation of the gap junction β-2 (GJB2) gene are important causes of sensorineural hearing loss (SNHL). This study aims to determine if congenital CMV infection leads to deafness by inducing GJB2 mutation. Methods: GJB2 gene sequencing and auditory brainstem response testing were performed in 159 neonates (63 with and 96 without CMV infection) from August 2008 to August 2011. For neonates with GJB2 mutation, their parents were further screened for GJB2 sequence. results: The incidence of SNHL was 12.7% in CMV-infected but 0% in uninfected children aged 1-1.5 y (P = 0.000). Similar mutation rates of the GJB2 gene were observed in neonates with or without CMV infection (34.9 vs. 32.3%, respectively, P = 0.734). No significant difference in the mutation rate of GJB2 was found among neonates with CMV infection and SNHL, those with CMV infection and normal hearing, and uninfected newborns with normal hearing (P = 0.438). Mutations 79G>A, 109G>A, 341A>G, and 608T>C were found in neonates with and without CMV infection. All of the above mutations were also found in both or one of the corresponding parents. conclusion: Congenital CMV infections may cause deafness in neonates, but this might be independent of GJB2 gene mutation.

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Section: Discussioncontrasting

confidence: 73%

mentioning

confidence: 99%

Does congenital cytomegalovirus infection lead to hearing loss by inducing mutation of the GJB2 gene?

Li¹,

Tan²,

Zhou³

et al. 2013

Pediatr Res

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show abstract

“…NES is associated with cytoplasmic trafficking in NPCs and plays an important role in the distribution and organization of critical cellular factors regulating cell proliferation and differentiation (39,53). Additionally, NES is located at 1q23 (an area that has been shown to be targeted selectively by HCMV) (42). Therefore, the downregulation of NES (and perhaps other neural genes) may be related to the selective effect of HCMV at 1q23.…”

Section: Discussionmentioning

confidence: 99%

Human Cytomegalovirus Infection Causes Premature and Abnormal Differentiation of Human Neural Progenitor Cells

Luo

Hannemann

Kulkarni

et al. 2010

J Virol

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101

162

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Congenital human cytomegalovirus (HCMV) infection is a leading cause of birth defects, largely manifested as central nervous system (CNS) disorders. The principal site of manifestations in the mouse model is the fetal brain's neural progenitor cell (NPC)-rich subventricular zone. Our previous human NPC studies found these cells to be fully permissive for HCMV and a useful in vitro model system. In continuing work, we observed that under culture conditions favoring maintenance of multipotency, infection caused NPCs to quickly and abnormally differentiate. This phenotypic change required active viral transcription. Whole-genome expression analysis found rapid downregulation of genes that maintain multipotency and establish NPCs' neural identity. Quantitative PCR, Western blot, and immunofluorescence assays confirmed that the mRNA and protein levels of four hallmark NPC proteins (nestin, doublecortin, sex-determining homeobox 2, and glial fibrillary acidic protein) were decreased by HCMV infection. The decreases required active viral replication and were due, at least in part, to proteasomal degradation. Our results suggest that HCMV infection causes in utero CNS defects by inducing both premature and abnormal differentiation of NPCs.Congenital human cytomegalovirus (HCMV) infection is a leading cause of birth defects, primarily affecting the central nervous system (CNS). Primary infection during pregnancy poses a 30 to 40% risk of intrauterine transmission, with severe adverse outcomes more likely if the infection occurs within the first half of gestation (46). Each year, approximately 1% of all newborns are congenitally infected with HCMV. Approximately 5 to 10% of these infants manifest signs of serious neurological defects at birth, including deafness, mental retardation, blindness, microencephaly, hydrocephalus, and cerebral calcification (2,4,65). In addition, 10 to 15% of congenitally infected infants who are asymptomatic at birth subsequently develop brain disorders such as sensorineural hearing loss (12, 47, 52). Moreover, accumulating evidence suggests that more subtle changes in human brain development, such as autism and language development, may be related to congenital HCMV infection (68,76,77).Although HCMV can infect a wide range of tissues in vivo (61), the fetal brain is the principal site of the deleterious manifestations of infection. It has been suggested that the severity of neuropathological changes and clinical outcomes may be associated with the stage of CNS development at which congenital infection occurs, with early-gestation infections producing more severe outcomes (3, 46). However, the mechanism of HCMV pathogenesis in the developing CNS remains poorly understood. Studies of HCMV in human subjects have obvious limitations; therefore, model systems of both in vitro and in vivo HCMV infections have been devised to provide insights into infection of the developing brain.Congenital infection studies have been performed principally with the mouse model. Studies of mice revealed that very ea...

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“…Our previous studies have shown that HCMV can inflict site-specific chromosomal damage in the form of double-strand breaks (DSBs) (13,30). DSBs can be repaired without error by homology-directed repair (HDR) or by error-prone mechanisms such as nonhomologous end-joining or single-strand annealing (34,42).…”

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confidence: 99%

Stimulation of Homology-Directed Repair at I-SceI-Induced DNA Breaks during the Permissive Life Cycle of Human Cytomegalovirus

Kulkarni

Fortunato

2011

J Virol

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Human cytomegalovirus (HCMV) selectively relocalizes many DNA repair proteins, thereby avoiding a potentially detrimental damage response. In the present study, we evaluated interactions between HCMV and the homology-directed repair (HDR) pathway. In permissive human foreskin fibroblasts, a fluorescence-based doublestranded break repair assay was used to determine that HCMV stimulated HDR. Repair of both stably integrated and extrachromosomal reporter substrates was observed to increase. HDR was also stimulated through individual expression of the viral immediate-early protein IE1-72, mimicking full virus infection. These experiments further demonstrate HCMV's role in modulating critical cellular processes during a permissive infection.

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Human cytomegalovirus (HCMV) and hearing impairment: Infection of fibroblast cells with HCMV induces chromosome breaks at 1q23.3, between loci DFNA7 and DFNA49—Both involved in dominantly inherited, sensorineural, hearing impairment

Cited by 29 publications

References 32 publications

Does congenital cytomegalovirus infection lead to hearing loss by inducing mutation of the GJB2 gene?

Does congenital cytomegalovirus infection lead to hearing loss by inducing mutation of the GJB2 gene?

Human Cytomegalovirus Infection Causes Premature and Abnormal Differentiation of Human Neural Progenitor Cells

Stimulation of Homology-Directed Repair at I-SceI-Induced DNA Breaks during the Permissive Life Cycle of Human Cytomegalovirus

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