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Mutations in COL11A2 cause non-syndromic hearing loss (DFNA13)

Abstract

We report that mutation of COL11A2 causes deafness previously mapped to the DFNA13 locus on chromosome 6p. We found two families (one American and one Dutch) with autosomal dominant, non-syndromic hearing loss to have mutations in COL11A2 that are predicted to affect the triple-helix domain of the collagen protein. In both families, deafness is non-progressive and predominantly affects middle frequencies. Mice with a targeted disruption of Col11a2 also were shown to have hearing loss. Electron microscopy of the tectorial membrane of these mice revealed loss of organization of the collagen fibrils. Our findings revealed a unique ultrastructural malformation of inner-ear architecture associated with non-syndromic hearing loss, and suggest that tectorial membrane abnormalities may be one aetiology of sensorineural hearing loss primarily affecting the mid-frequencies.

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Figure 1: American DFNA13 family.
Figure 2: Dutch DFNA13 family.
Figure 3: Physical map of RING1, RXRB and COL11A2 are expressed in a human fetal cochlear cDNA library; HKE4 (RING5) and HKE6 (RING2) are not.
Figure 4: COL11A2 mutation in the American family.
Figure 5: COL11A2 mutation in the Dutch family.
Figure 6: Wild-type mouse strain FVB/N.
Figure 7: Col11a2–/– mice.
Figure 8: In situ hybridization analysis of Col11a2 expression within the mouse inner ear.

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Acknowledgements

We thank B. Robinson for technical assistance; S. Sullivan, D. Wu and D. Anderson for technical advice; and T. Friedman and R. Morell for comments and suggestions. Supported in part by NIH Otolaryngology Research Training Grant 5-T32-DC00040 (W.T.M.), Heinsius Houbolt Foundation, Nijmegan KNO Research Fund, NIH intramural research fund Z01-DC00054-01 (A.J.G.) and RO1-DC03544 (R.J.H.S.).

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Correspondence to Richard J.H. Smith.

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McGuirt, W., Prasad, S., Griffith, A. et al. Mutations in COL11A2 cause non-syndromic hearing loss (DFNA13) . Nat Genet 23, 413–419 (1999). https://doi.org/10.1038/70516

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