2. Academic Validation
  3. Inframe deletion of human ESPN is associated with deafness, vestibulopathy and vision impairment

Inframe deletion of human ESPN is associated with deafness, vestibulopathy and vision impairment

  • J Med Genet. 2018 Jul;55(7):479-488. doi: 10.1136/jmedgenet-2017-105221.
Zubair M Ahmed 1,  Thomas J Jaworek # 1,  Gowri N Sarangdhar # 2,  Lili Zheng 3,  Khitab Gul 2,  Shaheen N Khan 4,  Thomas B Friedman 5,  Robert A Sisk 2 6,  James R Bartles 3,  Sheikh Riazuddin 7 8,  Saima Riazuddin 1 7
Affiliations

Affiliations

  • 1 Department of Otorhinolaryngology Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, Maryland, USA.
  • 2 Abrahamson Pediatric Eye Institute, Cincinnati Children's Hospital, Cincinnati, Ohio, USA.
  • 3 Department of Cell and Molecular Biology, School of Medicine, Northwestern University Feinberg, Chicago, Illinois, USA.
  • 4 Center for Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan.
  • 5 Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorder, National Institutes of Health, Bethesda, Maryland, USA.
  • 6 Ophthalmology, Cincinnati Eye Institute, Cincinnati, Ohio, USA.
  • 7 Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad, Pakistan.
  • 8 University of Lahore and Allama Iqbal Medical Research Centre, Jinnah Hospital Complex, Lahore, Pakistan.
  • # Contributed equally.
PMID: 29572253 DOI: 10.1136/jmedgenet-2017-105221
Abstract

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.

Keywords

deafness; usher syndrome; vision impairment.

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