Human Molecular Genetics, Vol 8, 1431-1441, Copyright © 1999 by Oxford University Press
I Yajima, S Sato, T Kimura, K Yasumoto, S Shibahara, CR Goding and H Yamamoto
Waardenburg syndrome type 2 (WS2) is an autosomal dominant disorder
characterized by a combination of pigmentary and auditory abnormalities.
Approximately 20% of WS2 cases are associated with mutations in the gene
encoding microphthalmia-associated transcription factor (MITF). MITF plays
a critical role in the development of both neural-crest-derived melanocytes
and optic cup-derived retinal pigmented epithelium (RPE); the loss of a
functional Mitf in mice results in complete absence of all pigment cells,
which in turn induces microphthalmia and inner ear deafness. The black-eyed
white Mitf mi-bw homozygous mouse normally has a pigmented RPE but lacks
melanocytes essential for the pigmentation of the body and hearing. We show
here that Mitf mi-bw is caused by an insertion into intron 3 of a 7.2 kb
novel L1 element, L1bw, which belongs to an actively retrotransposing TF
subfamily. The L1bw insertion reduces the amount of mRNAs for two Mitf
isoforms, Mitf-A and Mitf-H, by affecting their overall expression levels
and pre-mRNA splicing patterns, while it abolishes mRNA expression of
another isoform, Mitf-M, which is specifically expressed in
neural-crest-derived melanocytes. The consequence of the L1 insertion in
the black-eyed white Mitf mi-bw mouse is that the developmental programme
for RPE cells proceeds normally, most likely because of the presence of
residual, full-length Mitf-A and Mitf-H proteins, whereas the lack of
Mitf-M results in loss of the melanocyte population. The results suggest
that melanocyte development depends critically on a single Mitf isoform,
Mitf-M, and raise the possibility that specific mutations affecting MITF-M,
the human equivalent of Mitf- M, may be responsible for a subset of WS2
conditions.
ARTICLES
An L1 element intronic insertion in the black-eyed white (Mitf[mi-bw]) gene: the loss of a single Mitf isoform responsible for the pigmentary defect and inner ear deafness
Biological Institute, Graduate School of Science, Tohoku University, Sendai, Miyagi 980-8578, Japan,
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