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.
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.
Yajima
I
I
Biological Institute, Graduate School of Science, Tohoku University, Sendai, Miyagi 980-8578, Japan,
Sato
S
S
Kimura
T
T
Yasumoto
K
K
Shibahara
S
S
Goding
C R
CR
Yamamoto
H
H
D000483:Alleles; D000818:Animals; D001483:Base Sequence; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D014644:Genetic Variation; D006319:Hearing Loss, Sensorineural / Q000235:genetics; D006801:Humans; D007438:Introns / Q000235:genetics*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D051739:Microphthalmia-Associated Transcription Factor; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D010641:Phenotype; D010859:Pigmentation Disorders / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics; D018626:Retroelements; D012880:Skin Pigmentation / Q000235:genetics; D014157:Transcription Factors; D014849:Waardenburg Syndrome / Q000235:genetics
D004268:DNA-Binding Proteins; C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor; C497235:Mitf protein, mouse; D020033:Protein Isoforms; D018626:Retroelements; D014157:Transcription Factors