EYA1 and SIX1 gene mutations in Japanese patients with branchio-oto-renal (BOR) syndrome and related conditions.
We isolated genomic DNA from 15 patients with branchio-oto-renal (BOR) syndrome or BOR-related conditions. Seven patients had BOR syndrome (two familial and five sporadic), and eight had deafness and renal malformations without branchial fistula (BOR-related conditions). We analyzed all exons and exon-intron boundaries of EYA1 and SIX1 using the polymerase chain reaction (PCR) direct sequencing, and characterized their mutations. In some patients, analysis of mRNA by reverse transcription (RT)-PCR was performed to examine whether the mutation affects the mRNA splicing. We identified five novel disease-causing heterozygous EYA1 mutations in five patients with BOR syndrome (two familial and three sporadic, 5/7=71%), but EYA1 and SIX1 mutations were not detected in the other two patients with BOR syndrome or any of the patients with BOR-related conditions. The detected EYA1 mutations were two nonsense mutations, two splicing acceptor-site mutations, and a point mutation (G>T) of the first base of exon 10. Analysis of mRNA by RT-PCR direct sequencing revealed that the latter point mutation led to the skipping of exon 10. In conclusion, (1) EYA1 mutations are a major cause of BOR syndrome in Japanese, (2) EYA1 and SIX1 mutations were not a major cause of BOR-related conditions, (3) we demonstrated for the first time that the point mutation (G>T) of the first base of the exon in EYA1 gene induced exon skipping.
Okada
Michiyo
M
Department of Clinical Genetics and Molecular Medicine, National Center for Child Health and Development, Tokyo, Japan.
Fujimaru
Rika
R
Morimoto
Noriko
N
Satomura
Kenichi
K
Kaku
Yoshikazu
Y
Tsuzuki
Kazuo
K
Nozu
Kandai
K
Okuyama
Torayuki
T
Iijima
Kazumoto
K
D000015:Abnormalities, Multiple / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D001934:Branchial Region / Q000002:abnormalities*; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004423:Ear / Q000002:abnormalities*; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D007564:Japan; D007668:Kidney / Q000002:abnormalities*; D008297:Male; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D017027:Protein Tyrosine Phosphatases / Q000235:genetics*; D013577:Syndrome
D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; C099236:SIX1 protein, human; C104381:EYA1 protein, human; D017027:Protein Tyrosine Phosphatases