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Inframe deletion of human ESPN is associated with deafness, vestibulopathy and vision impairment
  1. Zubair M Ahmed1,
  2. Thomas J Jaworek1,
  3. Gowri N Sarangdhar2,
  4. Lili Zheng3,
  5. Khitab Gul2,
  6. Shaheen N Khan4,
  7. Thomas B Friedman5,
  8. Robert A Sisk2,6,
  9. James R Bartles3,
  10. Sheikh Riazuddin7,8,
  11. Saima Riazuddin1,7
  1. 1 Department of Otorhinolaryngology Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, Maryland, USA
  2. 2 Abrahamson Pediatric Eye Institute, Cincinnati Children’s Hospital, Cincinnati, Ohio, USA
  3. 3 Department of Cell and Molecular Biology, School of Medicine, Northwestern University Feinberg, Chicago, Illinois, USA
  4. 4 Center for Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan
  5. 5 Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorder, National Institutes of Health, Bethesda, Maryland, USA
  6. 6 Ophthalmology, Cincinnati Eye Institute, Cincinnati, Ohio, USA
  7. 7 Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad, Pakistan
  8. 8 University of Lahore and Allama Iqbal Medical Research Centre, Jinnah Hospital Complex, Lahore, Pakistan
  1. Correspondence to Professor Zubair M Ahmed, Department of Otorhinolaryngology Head and Neck Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA; zmahmed{at}


Background Usher syndrome (USH) is a neurosensory disorder characterised by deafness, variable vestibular areflexia and vision loss. The aim of the study was to identify the genetic defect in a Pakistani family (PKDF1051) segregating USH.

Methods Genome-wide linkage analysis was performed by using an Illumina linkage array followed by Sanger and exome sequencing. Heterologous cells and mouse organ of Corti explant-based transfection assays were used for functional evaluations. Detailed clinical evaluations were performed to characterise the USH phenotype.

Results Through homozygosity mapping, we genetically linked the USH phenotype segregating in family PKDF1051 to markers on chromosome 1p36.32-p36.22. The locus was designated USH1M. Using a combination of Sanger sequencing and exome sequencing, we identified a novel homozygous 18 base pair inframe deletion in ESPN. Variants of ESPN, encoding the actin-bundling protein espin, have been previously associated with deafness and vestibular areflexia in humans with no apparent visual deficits. Our functional studies in heterologous cells and in mouse organ of Corti explant cultures revealed that the six deleted residues in affected individuals of family PKDF1051 are essential for the actin bundling function of espin demonstrated by ultracentrifugation actin binding and bundling assays. Funduscopic examination of the affected individuals of family PKDF1051 revealed irregular retinal contour, temporal flecks and disc pallor in both eyes. ERG revealed diminished rod photoreceptor function among affected individuals.

Conclusion Our study uncovers an additional USH gene, assigns the USH1 phenotype to a variant of ESPN and provides a 12th molecular component to the USH proteome.

  • deafness
  • vision impairment
  • usher syndrome

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  • TJJ and GNS contributed equally.

  • Contributors ZMA and SaR conceived and designed the study. ZMA, TJJ, GNS, KG, LZ and JRB performed experiments. ZMA, TJJ, LZ, RAS, GNS, KG and JRB analysed data. SNK, ShR and TBF ascertained the family and contributed reagents and materials. ZMA, TJJ, GNS, LZ, JRB and SaR prepared the figures. ZMA and SaR wrote the paper, and all the coauthors edited the manuscript and approved final submission.

  • Funding This study has been supported by grants from: the National Institutes of Health (NIH) – National Institute on Deafness and Other Communication Disorders (NIDCD) R56DC011803, R01DC016295 (to SaR and ZMA) and R01DC004314 (to JRB). This work was supported (in part) by NIDCD/NIH Intramural Program funds DC000039-15 (to TBF).

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval Approval for this study was obtained from the following institutional review boards (IRBs): the National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan, the Combined Neuroscience Institutional Review Board (OH-93-N-016) and the University of Maryland School of Medicine, USA (HP-00061036).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement Variant found in PKDF1051 has been deposited in ClinVar database.