Biology Reference
In-Depth Information
3
Mapping and Cloning of Genes for
Inherited Hearing Impairment
ROBERT F. M UELLER,GUY VAN CAMP and NICK J. L ENCH
1. Introduction
The last few years have seen rapid progress in the mapping and cloning of
genes for syndromic and nonsyndromic inherited hearing impairment.
Gene cloning can involve a number of different approaches, which include
functional, candidate, positional, and positional candidate cloning.
Functional cloning was the first method used to clone human genes.
It involves studying cells or tissues affected by the disorder, identifying
an altered protein or transcript specific to that tissue, and using this infor-
mation to design a DNA probe to identify and isolate the gene respon-
sible. The structural complexity of the inner ear, along with the large
number of different proteins expressed within it, has seriously limited the
use of this approach in the identification of genes for inherited hearing
impairment.
The candidate gene approach involves screening genes that have been
characterized and, because of knowledge about their function (or likely
function) and/or pattern of expression, are thought to be responsible for
the disorder even in the absence of information on their location in the
genome. This approach was used in the identification of one of the genes
responsible for the syndromic form of inherited hearing impairment known
as Alport syndrome. Alport syndrome is characterized by the combination
of glomerulonephritis and progressive high-frequency sensorineural hear-
ing impairment. Both the renal involvement and hearing impairment
usually manifest in adolescence or early adult life. Alport syndrome is
genetically heterogeneous with autosomal dominant, recessive, and X-
linked patterns of inheritance reported, the latter being the most common
form. Immunological studies of renal biopsies from individuals with Alport
syndrome showed renal glomerular basement membrane abnormalities of
the third (
COL4A3
), fourth (
COL4A4
) and fifth (
COL4A5
) alpha chains
of type IV collagen (Kashtan et al. 1986; Kleppel et al. 1987). The
COL4A5
gene mapped to the X chromosome (Vetrie et al. 1992) suggested it as a
likely candidate gene which was confirmed by identification of mutations
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