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Two recent studies independently report mutations in the otoferlin (OTOF) gene are the cause of a rare temporary hearing loss caused by a high body temperature.

Ear-120px

I have a hearing loss, and if I spot research on deafness when updating papers for my own research (see Footnote of previous post) I often take a peek.

Tonight I learnt that some people have deafness that is dependent on their body temperature, with a high temperature (say, a fever) inducing deafness. They recover some time after their body temperature has returned to normal.

In some ways it’s quite quirky, but knowing how molecules interact I can imagine how this might be possible.

The study I ran into was a Chinese study examining a collection of 73 Han Chinese patients with auditory neuropathy*. During this study, they uncovered a case of temperature-dependent hearing loss:

However, his hearing was affected by a slight change of body temperature. His mother found that his hearing in the morning is generally better than in the afternoon, and temperature measurements showed that his body temperature in the afternoon was generally 0.1-0.6˚ [˚C?] higher than that in the morning.

They tested his hearing loss, raising his body temperature during an extended hospital visit and found that

When his body temperature rose above 36.5°C, the boy’s hearing loss was severe (70-80dB HL) and this symptom could last for a whole day.

The aim of their work was to screen Han Chinese auditory neuropathy patients for defects in the OTOF gene, as this gene has previously been shown to be involved in other forms of severe hearing loss and previous studies had studied other populations. Only 4 of the patients showed mutations in OTOF, including the boy with the temperature-dependent hearing loss.

The boy with the temperature-dependent hearing loss had two variant OTOF genes, one from each parent. Both parents had one variant and one normal copy of the OTOF gene; their son’s OTOF genes were both variant.** These variants were not seen the 92 normal-hearing people.

Calcium binding (C2) domain (Source: Wikimedia Commons.)

Calcium binding (C2) domain (Source: Wikimedia Commons.)

One of the two variant alleles is a so-called nonsense mutation, terminating the gene early so that this allele is unlikely to be functional. The other is a missense mutation, altering the amino acid at one position in the protein the gene codes, just after the fifth of six domains in the protein that bind calcium.

An earlier research study also offers a mutant OTOF gene as possibly being an allele that causes temperature-sensitive auditory neuropathy. (See Reference 3.)

Temperature-sensitive hearing loss was new to me, so I had a quick look in research literature using PubMed to see if there were other papers about this.

I found that published just a month or so before the Chinese study is another report from a French group studying a family with three children with at temperature-sensitive hearing loss. Using a genetic marker screen,*** then sequencing the protein-encoding regions of the OTOF gene (including the intron-exon boundaries) they found a missense mutation in the sixth (last) calcium-binding domain of the OTOF gene.

The atomic structure of the calcium-binding domains found in the OTOF gene are known; I’ve shown a cartoon of it in the illustration above. It would be interesting to look where the mutations found are within the structure of the domains and how they might affect the function of this part of the protein using molecular modelling.****

Footnotes

* More fully: non-syndromic auditory neuropathy, meaning that the hearing loss was not part of a disease with other symptoms (a syndromic disease) and that the hair cells function, but the signal is not transmitted to the brain and thus the hearing loss can be thought of as a pathology (pathy) of the neurons (nerve cells, neuro; see lower-right of illustration below).

Auditory system (Source: Emergent Cognition through Active Perception website.)

Auditory system (Source: Emergent Cognition through Active Perception website.)

** Leaving aside genes on the sex chromosomes, we have two copies of each gene. Here the parents were heterozygous, having a mixture of two different alleles of the gene, one normal and one variant. By random chance about one-quarter of their children would be expected to get both of the variant alleles.

*** See my recent article Boney lumps, linkage analysis and whole genome sequencing for very brief outline of how genetic markers are used to identify regions of chromosomes that might be associated with a feature in the people being studied.

**** Molecular modelling was the basis of my earlier research work; most people today want me to look at genomes!

ReferencesResearchBlogging.org

Wang, D., Wang, Y., Weil, D., Zhao, Y., Rao, S., Zong, L., Ji, Y., Liu, Q., Li, J., Yang, H., Shen, Y., Benedict-Alderfer, C., Zheng, Q., Petit, C., & Wang, Q. (2010). Screening mutations of OTOF gene in Chinese patients with auditory neuropathy, including a familial case of temperature-sensitive auditory neuropathy BMC Medical Genetics, 11 (1) DOI: 10.1186/1471-2350-11-79 (Open access.)

This post was chosen as an Editor's Selection for ResearchBlogging.orgMarlin, S., Feldmann, D., Nguyen, Y., Rouillon, I., Loundon, N., Jonard, L., Bonnet, C., Couderc, R., Garabedian, E., & Petit, C. (2010). Temperature-sensitive auditory neuropathy associated with an otoferlin mutation: Deafening fever! Biochemical and Biophysical Research Communications, 394 (3), 737-742 DOI: 10.1016/j.bbrc.2010.03.062 (Subscription required.)

Varga, R. (2005). OTOF mutations revealed by genetic analysis of hearing loss families including a potential temperature sensitive auditory neuropathy allele Journal of Medical Genetics, 43 (7), 576-581 DOI: 10.1136/jmg.2005.038612 (Open access.)


Some other articles on Code for life looking at genetics:

The scale of cellular life and compacting chromosomes

Science bite: Longevity gene study has flaws?

Boney lumps, linkage analysis and whole genome sequencing

Autism genetics, how do you copy?

The inheritance of face recognition (should you blame your parents if you can’t recognise faces?)

Deleting a gene can turn an ovary into a testis in adult mammals