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

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

Research output: Contribution to journalArticle

98 Citations (Scopus)

Abstract

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, L1(bw), which belongs to an actively retrotransposing T(F) subfamily. The L1(bw), 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.

Original languageEnglish
Pages (from-to)1431-1441
Number of pages11
JournalHuman Molecular Genetics
Volume8
Issue number8
DOIs
Publication statusPublished - 1999 Aug 18
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

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. / Yajima, Ichiro; Sato, Shigeru; Kimura, Takaharu; Yasumoto, Ken Ichi; Shibahara, Shigeki; Goding, Colin R.; Yamamoto, Hiroaki.

In: Human Molecular Genetics, Vol. 8, No. 8, 18.08.1999, p. 1431-1441.

Research output: Contribution to journalArticle

Yajima, Ichiro ; Sato, Shigeru ; Kimura, Takaharu ; Yasumoto, Ken Ichi ; Shibahara, Shigeki ; Goding, Colin R. ; Yamamoto, Hiroaki. / 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. In: Human Molecular Genetics. 1999 ; Vol. 8, No. 8. pp. 1431-1441.
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abstract = "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, L1(bw), which belongs to an actively retrotransposing T(F) subfamily. The L1(bw), 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.",
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AU - Yajima, Ichiro

AU - Sato, Shigeru

AU - Kimura, Takaharu

AU - Yasumoto, Ken Ichi

AU - Shibahara, Shigeki

AU - Goding, Colin R.

AU - Yamamoto, Hiroaki

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N2 - 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, L1(bw), which belongs to an actively retrotransposing T(F) subfamily. The L1(bw), 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.

AB - 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, L1(bw), which belongs to an actively retrotransposing T(F) subfamily. The L1(bw), 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.

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