Regulatory Mutations in Human Hereditary Deafness

  • Jonathan E. Bird
  • Thomas B. FriedmanEmail author


Moderate to profound deafness is a common sensory deficit that is estimated by the World Health Organization to affect more than 275 million people worldwide (WHO 2010). The etiology of hearing loss is varied and can include environmental noise, physical trauma to the head, infections, ototoxic compounds, and the natural aging process. Heritable hearing loss segregating as a Mendelian trait is thought to constitute but a fraction of cases; nonetheless, its study has yielded rich information about the biology of hearing and its pathophysiology. This chapter is a critical review of gene regulation in the auditory system and draws upon the dissection of human hereditary nonsyndromic hearing loss and relevant animal models. This body of work encompasses mutant alleles of transcription factors, promoters, long-range enhancers, and microRNAs that have been associated with hearing loss including genes such as ESSRB, EYA4, GRHL2, HGF, MIR96, POU3F4, and POU4F3. At the conclusion of this chapter, we speculate how future studies can capitalize on new sequencing technologies to broaden our knowledge of gene regulation in both normal hearing and deafness.





3¢ untranslated region


Auditory brainstem response


Aldehyde dehydrogenase 1 family member A2


ATPase Na+/K + transporting, beta 2 polypeptide


Base pair


Cadherin-related 23


Chromatin immunoprecipitation


Chromatin immunoprecipitation coupled with massively parallel sequencing


Nonsyndromic deafness autosomal dominant


Nonsyndromic deafness autosomal recessive


Nonsyndromic deafness X-linked


Distortion product otoacoustic emissions


Embryonic day 17


Estrogen-related receptor


European conditional mouse mutagenesis project


Eyes absent Drosophila homolog 4


Fluorescence-activated cell sorting


F-box protein 11


Green fluorescent protein


Grainyhead-like 2


Hepatocyte growth factor


Highly conserved noncoding regions




Induced pluripotent stems cells




Potassium voltage-gated channel, Isk-related family, member 1


Potassium voltage-gated channel, KQT-like subfamily, member 1


NIH knockout mouse project




Mouse embryonic fibroblasts


Nonsense-mediated mRNA decay


POU class 3 homeobox 4


POU class 4 homeobox 3


POU homeodomain


Prostaglandin D2 synthase 21 kDa


Protein tyrosine phosphatase receptor type, Q


RNA-induced silencing complex


R-spondin 3


SIX homeobox 1


Solute carrier family 12 member 2


Solute carrier family 26 member 5


Single nucleotide polymorphism


Short tandem repeats


World Health Organization


Lysine-deficient protein kinase 4


Waardenburg syndrome type 2A



We thank Lisa Cunningham, Dennis Drayna, Ronna Hertzano, Robert Morell and Julie Schultz for helpful discussions. JEB and TBF were supported by the National Institute on Deafness and Other Communication Disorders intramural research funds DC000039-15 at the National Institutes of Health.


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© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Laboratory of Molecular GeneticsNational Institute on Deafness and Other Communication Disorders, National Institutes of HealthRockvilleUSA

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