Biology Reference
In-Depth Information
DMD
locus. However, II-10 has only an unaffected son, which does not
genetically confirm her carrier status (Pfister et al. 1998).
Unlike
DMD
patients,
DFN4
-affected individuals had no gross rearrange-
ments of the 79-exon dystrophin gene in Southern blot and PCR analyses.
DFN4
males show no clinical characteristics of Duchenne muscular dystro-
phy, and there are no data indicating that patients with DMD or Becker mus-
cular dystrophy have sensorineural hearing loss. However, the
mdx
mouse
has a nonsense mutation in exon 23 of
Dmd
and sensorineural hearing loss
as measured by ABR analysis (Raynor and Mulroy 1997). A structural role
for dystrophin in the auditory system is consistent with its expression in the
organ of Corti, where it has been localized by immunohistochemistry to
the lateral membrane and cuticular plate of the hair cells.
DMD
therefore
remains a candidate for
DFN4
(Dodson et al. 1995).
3.18 DFN6
A clinically distinct X-linked progressive, nonsyndromic, sensorineural deaf-
ness was described in a five-generation Spanish family with ten affected
males. Hearing loss in this family did not show linkage to the other DFN loci,
and was then mapped by linkage analysis to Xp22 and refined by haplotype
analysis to a 15 cM interval (del Castillo et al. 1996). Males begin showing a
high-frequency loss at age 5 to 7 years that progresses to profound deafness.
Seven of the ten carrier females have a moderate hearing loss with the onset
delayed until 40 years of age. The affection status of other family members
who are now under the age of 5 years may eventually be definitively estab-
lished, at which time their genotypes may allow further refinement of the
map position of
DFN6
and the eventual identification of this gene.
3.19 Evidence for Digenic Inheritance of Nonsyndromic
Hearing Loss
Mutations of a single gene can explain the hearing loss in the majority of
DFN, DFNA and DFNB families that have been ascertained. However,
there are two reports of familial hearing loss that suggest a pattern of inher-
itance involving two loci (digenic inheritance). The first example is a small
consanguineous family with three affected and three unaffected siblings. A
genome-wide screen identified two regions of homozygosity-by-descent
shared by the three affected children on 3q21.3-q25.2 (Lod = 2.78) and
19p13.3-p13.1 (Lod = 2.78). The authors speculated that homozygosity for
two nonallelic recessive mutations may account for the profound congeni-
tal deafness in this family (Chen et al. 1997).
The second possible example of digenic inheritance is a Swedish family
segregating nonsyndromic, postlingual, progressive sensorineural hearing
loss. Initial pedigree analysis suggested that a single autosomal dominant
mutation could account for the observed inheritance of hearing loss, which
