Journal Article

An L1 Element Intronic Insertion in the <i>Black-Eyed White (Mitf<sup><i>mi-bw</i></sup></i>) Gene: The Loss of a Single Mitf Isoform Responsible for the Pigmentary Defect and Inner Ear Deafness

Ichiro Yajima, Shigeru Sato, Takaharu Kimura, Ken-ichi Yasumoto, Shigeki Shibahara, Colin R. Goding and Hiroaki Yamamoto

in Human Molecular Genetics

Volume 8, issue 8, pages 1431-1441
Published in print August 1999 | ISSN: 0964-6906
Published online August 1999 | e-ISSN: 1460-2083 | DOI:
An L1 Element Intronic Insertion in the Black-Eyed White (Mitfmi-bw) Gene: The Loss of a Single Mitf Isoform Responsible for the Pigmentary Defect and Inner Ear Deafness

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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 Mitfmi-bw homozygous mouse normally has a pigmented RPE but lacks melanocytes essential for the pigmentation of the body and hearing. We show here that Mitfmi-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 Mitfmi-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.

Journal Article.  8768 words.  Illustrated.

Subjects: Genetics and Genomics

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