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.
Human cytomegalovirus (HCMV) infection is the most common congenital infection in developed countries and is responsible for a substantial fraction of sensorineural hearing impairment (SNHI) in children. The risk of hearing impairment is associated with viral load in urine and blood collected during the first postnatal month. However, although inner ear abnormalities are observed in some children with HCMV-induced SNHI, the exact mechanism whereby congenital HCMV infection causes hearing impairment is unknown. Earlier studies using standard cytogenetic mapping techniques showed that infection of S-phase human fibroblast cells with HCMV resulted in two specific, site-directed, chromosome breaks at band positions 1q21 and 1q42 which include loci involved in dominantly and recessively inherited hearing impairment, respectively. These findings suggested that cells infected with HCMV might provide a reservoir for genetic damage and, in a clinical perspective, a scenario could be envisioned whereby hearing impairment could result from early DNA damage of dividing fetal cells rather than viral replication and cell lysis. In this work we demonstrate, using fine mapping techniques, that HCMV infection in S-phase fibroblast cells induces genetic damage at 1q23.3, within a maximal region of 37 kb, containing five low copy repeat (LCR) elements. The breakpoint is situated between two hearing impairment (HI) loci, DFNA49 and DFNA7, and in close proximity to the MPZ gene previously shown to be involved in autosomal dominant Charcot-Marie-Tooth syndrome (CMT1B) with auditory neuropathy.
Nystad
Mona
M
Department of Medical Genetics, University Hospital of North-Norway, N-9038, Tromsø, Norway.
Fagerheim
Toril
T
Brox
Vigdis
V
Fortunato
Elizabeth A
EA
Nilssen
Øivind
Ø
D019457:Chromosome Breakage; D002874:Chromosome Mapping; D002878:Chromosomes, Human, Pair 1; D003586:Cytomegalovirus Infections / Q000235:genetics*; D005347:Fibroblasts / Q000821:virology; D006309:Hearing / Q000235:genetics*; D006319:Hearing Loss, Sensorineural / Q000235:genetics*; D006801:Humans; D008957:Models, Genetic; D012091:Repetitive Sequences, Nucleic Acid