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Publication Detail
Mutations and altered expression of SERPINF1 in patients with familial otosclerosis.
  • Publication Type:
    Journal article
  • Publication Sub Type:
  • Authors:
    Ziff JL, Crompton M, Powell HR, Lavy JA, Aldren CP, Steel KP, Saeed SR, Dawson SJ
  • Publication date:
  • Journal:
    Human molecular genetics
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  • Print ISSN:
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  • Addresses:
    UCL Ear Institute, University College London, London, WC1X 8EE, UK.
Otosclerosis is a relatively common heterogenous condition, characterised by abnormal bone remodelling in the otic capsule leading to fixation of the stapedial footplate and an associated conductive hearing loss. Although familial linkage and candidate gene association studies have been performed in recent years, little progress has been made in identifying disease-causing genes. Here, we used whole-exome sequencing in four families exhibiting dominantly-inherited otosclerosis to identify 23 candidate variants (reduced to 9 after segregation analysis) for further investigation in a secondary cohort of 84 familial cases. Multiple mutations were found in theSERPINF1(Serpin Peptidase Inhibitor, Clade F) gene which encodes PEDF (pigment epithelium derived factor), a potent inhibitor of angiogenesis and known regulator of bone density.Six rare heterozygousSERPINF1variants were found in 7 patients in our familial otosclerosis cohort; 3 are missense mutations predicted to be deleterious to protein function. The other 3 variants are all located in the 5'UTR of an alternative spliced transcriptSERPINF1-012 RNA-seq analysis demonstrated that this is the majorSERPINF1transcript in human stapes bone. Analysis of stapes from 2 patients with the 5'UTR mutations showed that they had reduced expression ofSERPINF1-012 All three 5'UTR mutations are predicted to occur within transcription factor binding sites and reporter gene assays confirmed that they affect gene expression levels. Furthermore, RT-qPCR analysis of stapes bone cDNA showed thatSERPINF1-012expression is reduced in otosclerosis patients with and withoutSERPINF1mutations suggesting it may be a common pathogenic pathway in the disease.
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