Refining the DFNB7–DFNB11 deafness locus using intragenic polymorphisms in a novel gene, TMEM2
Introduction
Severe congenital hearing impairment affects 0.1% of live-born infants and 1–2% of graduates of neonatal intensive care units (Marazita et al., 1993, Morton, 1991, Oudesluys-Murphy et al., 1996, Schein, 1980, Van Camp et al., 1997). Although deafness can be caused by a number of environmental and disease-related factors, in developed countries, at least 50% of cases are inherited (Reardon, 1992, Rose et al., 1977). Autosomal recessive non-syndromic hearing loss (ARNSHL) is the most common form of severe inherited childhood deafness. This genetically heterogeneous disorder can be caused by mutations in a number of different genes. To date, 28 ARNSHL loci (DFNB1–28) have been reported, and mutations in six genes — GJB2, MYO7A, MYO15, PDS, OTOF and TECTA — have been shown to cause ARNSHL (Kelsell et al., 1997, Li et al., 1998, Liu et al., 1997, Van Camp and Smith, 1999, Wang et al., 1998, Weil et al., 1997).
Five families have been described with ARNSHL linked to the DFNB7 and DFNB11 loci on chromosome 9q13–q21 (Greinwald et al., 1997, Jain et al., 1995, Scott et al., 1996). Although these loci were reported originally to map to different regions of chromosome 9, the correct placement of key markers defined a region shared by both DFNB7 and DFNB11 families (Greinwald et al., 1997), suggesting that mutations in a single gene are responsible for the DFNB7–DFNB11 hearing loss.
The DFNB7–DFNB11 interval on chromosome 9 is syntenic to that portion of mouse chromosome 19 associated with the dn mouse deafness locus (Jain et al., 1995), suggesting that these defects may be caused by mutations in orthologous genes (Jain et al., 1995, Keats et al., 1995). The dn/dn mouse mutant, which arose spontaneously from the curly-tail stock (ct), has ultrastructural abnormalities of the inner hair cells at birth, and by post-natal day 20, the organ of Corti is degenerated, and the inner and outer hair cells are lost (Bock and Steel, 1983, Dole and Kocher, 1958, Keats et al., 1995, Pujol et al., 1983). Backcross experiments and fluorescence in-situ hybridization (FISH) have demonstrated a chromosomal inversion at the dn locus (Viñas et al., 1998).
In this report, we describe the identification of a novel cochlear-expressed gene, TMEM2, which is located in the DFNB7–DFNB11 interval in humans and whose murine orthologue (Tmem2) maps to the dn region. The genomic structure and expression pattern of this gene are described, as are the results of a TMEM2 /Tmem2 mutation screen in DFNB7–DFNB11 families and dn mice.
Section snippets
Computer analysis
Nucleotide/protein homology searches were performed using the BLAST algorithm accessible through the National Center for Biotechnology Information (http://www.ncbi.nlm.nih.gov/). Screens for putative transmembrane domains within the TMEM2 protein were performed using the TMpred program at EMBnew.ch (http://www.ch.embnet.org/cgi-bin/TMPRED_form_parser/), the SOSUI transmembrane prediction program at Tokyo University of Agriculture & Technology (http://azusa.proteome.bio.tuat.ac.jp/sosui/) and
Sequence determination of a candidate gene in the DFNB7–DFNB11 interval
Several genes and unknown transcripts map to the DFNB7–DFNB11 interval (Greinwald et al., 1997, Scott et al., 1998). One of the unknown transcripts in the interval is represented by DNA marker stSG1345. Sequence analysis of IMAGE clone 84952, from which stSG1345 was derived, revealed a small open reading frame but no polyadenylation signal. When this sequence was analyzed using the BLAST algorithm, only a portion of the open reading frame showed a significant homology to other ESTs, suggesting
Conclusion
- 1.
Human TMEM2 is a novel gene within the DFNB7–DFNB11 interval. The gene encodes for a predicted protein product of 1383 amino acids that contains at least one putative transmembrane domain.
- 2.
The mouse homologue, Tmem2, is located in the dn interval of mouse chromosome 19.
- 3.
TMEM2 is expressed in human cochlea and a wide variety of other human tissues, although transcripts were not detectable in testis or ovary. In mice, Tmem2 is expressed in heart, brain, spleen, lung, liver skeletal muscle and
Acknowledgements
This work was supported by NIH grants P01DC00379 (B.K.), HG00457 (V.C.S.), the Roy J. Carver Charitable Trust (V.C.S.) and RO1DC02842 (R.J.H.S.).
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