B651 - Do filaggrin truncation variants affect hearing - 01/05/2008

B number: 
Principal applicant name: 
Prof Ian Day (Not used 0, Not used 0)
Prof John Henderson (Not used 0, Not used 0), Dr Amanda J Hall (Not used 0, Not used 0)
Title of project: 
Do filaggrin truncation variants affect hearing?
Proposal summary: 

Do filaggrin truncation mutations affect hearing?

This hypothesis is stimulated by a 'case observation' of a proband with residual mild ichthyosis (which was more severe in childhood) and palmoplantar atopic dermatitis. The father is more severely affected. More extended family history is unknown. For ordinary sounds, the proband also has a hearing threshold which is considerably lower than most people, and this was confirmed in an analysis at Dundee University. The father is elderly and his hearing status indeterminate. The most obvious diagnosis would be of one of the common filaggrin truncation mutations causing the dermatological picture, although this has not been proven. Nonetheless, the 'filaggrin/hearing' hypothesis will stand even if this familial picture reflected some other gene. Filaggrin is expressed in skin. It is also expressed in the tympanic membrane (Broekaert 1995). It has also been noted to be expressed in middle ear cholesteatoma (Chao and Huang 1989). Truncating mutations lead to a reduction of filaggrin-keratin crosslinking and altered keratinization and hence to the dermatological picture described above. The high mutation frequency worldwide may simply reflect high mutational drive on account of the structure of the gene, in conjunction with non-lethality of inactivating changes; or there could be a selective advantage to the mutations. Sound transmission involves both the external auditory meatus and tympanic membrane between outer and middle ear, and middle ear. Any structural influence of filaggrin in these locations could lead to filaggrin mutations affecting hearing thresholds and related traits. Hearing and language have formed a crucial part of progression of the human species and relative to the average, better hearing could have conferred both communication and survival advantages. It might even continue to do so in the present day. The purpose of this request is to test whether hearing characteristics are associated with filaggrin gene status. Most subjects with a filaggrin mutation will be heterozygous rather than homozygous. It is suggested therefore to adopt a genetic model in which heterozygotes are tested against wildtype for mean of each relevant hearing trait, and to do descriptives for homozygotes but not to regard them as part of the primary test - this seems reasonable, since, for dermatological features, heterozygosity produces clinical features. The proposed target list of quantitiative traits are those identified by Amanda Hall: hearing threshold at Focus 9 and Focus 11; tympanometry data at Focus 9 and Focus 11 - particularly middle ear compliance and gradient and the acoustic reflex threshold; and lastly, likely as an ordinal analysis, tympanic membrane abnormalities coded from photographs at Focus 9. The analyses will be done using existing resources within the respiratory group, which has recently worked in depth with the FLG data.

Date proposal received: 
Thursday, 1 May, 2008
Date proposal approved: 
Thursday, 1 May, 2008
Primary keyword: