CMT 1B with auditory neuropathy: Human cytomegalovirus (HCMV) and hearing impair

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Mutat Res. 2007 Jul 25

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 M, Fagerheim T, Brox V, Fortunato EA, Nilssen O.

Department of Medical Genetics, University Hospital of North-Norway,

N-9038 Tromsø, Norway.

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 37kb, 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.