Mutation of a transcription factor, TFCP2L3, causes progressive autosomal dominant hearing loss, DFNA28.
We ascertained a large American family with an autosomal dominant form of progressive non-syndromic sensorineural hearing loss. After excluding linkage to known deafness loci, we performed a genome-wide scan and found linkage to marker GAAT1A4 on chromosome 8q22 (LOD=5.12 at theta=0), and this locus was designated DFNA28. Sequencing of six candidate genes in the 1.4 cM linked region identified a frameshift mutation (1609-1610insC) resulting in a premature translation stop codon in exon 14 of the gene TFCP2L3 (transcription factor cellular promoter 2-like 3). TFCP2L3 is a member of a family of transcription factor genes whose archetype is TFCP2, a mammalian homolog of the Drosophila gene grainyhead. Northern blot analyses and in situ hybridization studies show that mouse Tfcp2l3 is expressed in many epithelial tissues, including cells lining the cochlear duct, at embryonic day 18.5 and postnatal day 5.
Peters
Linda M
LM
Section on Human Genetics, Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Rockville, MD 20850, USA.
Anderson
David W
DW
Griffith
Andrew J
AJ
Grundfast
Kenneth M
KM
San Agustin
Theresa B
TB
Madeo
Anne C
AC
Friedman
Thomas B
TB
Morell
Robert J
RJ
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D000818:Animals; D015152:Blotting, Northern; D002648:Child; D002675:Child, Preschool; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D003001:Cloning, Molecular; D017931:DNA Primers / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D016368:Frameshift Mutation; D005799:Genes, Dominant; D008040:Genetic Linkage / Q000235:genetics; D006319:Hearing Loss, Sensorineural / Q000235:genetics*; D006801:Humans; D017403:In Situ Hybridization; D008137:Longitudinal Studies; D008297:Male; D051379:Mice; D008875:Middle Aged; D008969:Molecular Sequence Data; D010375:Pedigree; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000235:genetics*
D017931:DNA Primers; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C501906:TFCP2 protein, human; D014157:Transcription Factors