Molecular Genetic Pathogenesis
The proteins associated with USH1 and USH2 interact with one another. Both harmonin (product of USH1C) and whirlin contain PDZ domains that play a role in these interactions. If any one of the molecules in this "Usher interactome" is nonfunctional or absent, sensorineural degeneration occurs in the inner ear and the retina [Adato et al 2005, Reiners et al 2006, van Wijk et al 2006, Maerker et al 2008]. Another PDZ domain-containing protein, PDZD7, was identified as a result of a study of a child with nonsyndromic sensorineural hearing loss and a homozygous reciprocal translocation; protein-protein interaction studies indicated that PDZD7 is a part of the Usher protein network [Schneider et al 2009]. Pathogenic variants in PDZD7 have not yet been shown to cause Usher syndrome, but it has been suggested that PDZD7 pathogenic variants may act as modifiers of the retinal phenotype in individuals with USH2A. Additionally, an individual with USH2 and heterozygous pathogenic variants in USH2A and PDZD7 and another affected individual with heterozygous variants in ADGRV1 and PDZD7 were reported, leading to the suggestion of digenic inheritance [Ebermann et al 2010].
Whirlin interacts in vivo with usherin and ADGRV1, suggesting that these three proteins function as a multiprotein complex in both the stereocilia of the cochlear hair cells and the periciliary membrane complex of the retinal photoreceptor cells [Yang et al 2010].
WHRN (DFNB31)
Gene structure. The longest WHRN transcript (NM_015404.3) contains 12 exons and spans 101 kb of genomic sequence. For a detailed summary of gene and protein information, see Table A, Gene.
Pathogenic variants.
Ebermann et al [2007] identified a nonsense variant in exon 1 and an exon 2 splice donor site variant in affected members of a German family with USH2. However, no evidence of causal WHRN variants was found in a study of 195 individuals with Usher syndrome, suggesting that the percentage of people with Usher syndrome type 2D is small [Aller et al 2010]. To date, fewer than 20 USH2-causing WHRN variants have been reported.
Normal gene product. Whirlin is a scaffold protein and has a structure similar to harmonin (the USH1C gene product) with up to three PDZ domains and a proline-rich domain. It has multiple isoforms, including the C-terminal isoform (NP_001077354.2, 524 amino acids) and the long isoform (NP_056219.3, 907 amino acids). Both of these isoforms are found in the cochlea; only the long isoform is expressed in the retina.
Abnormal protein product. See Molecular Genetic Pathogenesis. All pathogenic variants associated with Usher syndrome type 2D affect only the long isoform of whirlin. The whirlin knockout mouse has early-onset hearing loss and retinal degeneration starting at age 28 months, and its photoreceptors and hair cells show mislocalization and reduced expression of both usherin and protein ADGRV1. Returning whirlin to this mouse via gene therapy restores normal localization and expression levels of all three proteins [Yang et al 2010, Zou et al 2011].
USH2A
Gene structure.
USH2A spans approximately 790 kb of genomic DNA and contains 72 exons [van Wijk et al 2004]. For a detailed summary of gene and protein information, see Normal gene product and Table A, Gene.
Pathogenic variants. More than 600 USH2A pathogenic variants have been documented. Initially it was thought that most variants were in the 21 exons originally described, with p.Glu767SerfsTer21 being the most common (16%) [Eudy et al 1998, Adato et al 2000, Dreyer et al 2000, Weston et al 2000, Leroy et al 2001, Nájera et al 2002]. However, many pathogenic variants have now been reported in exons 22-72 and in the flanking intronic sequences of all exons [Baux et al 2007, Baux et al 2014]. A deep intronic variant resulting in activation of a pseudoexon has also been found, indicating that RNA analysis may be informative in individuals for whom only one variant is identified by exome sequencing [Vaché et al 2012]. Four USH2A variants account for 64% of mutated alleles underlying USH2 in the non-Ashkenazi Jewish population [Auslender et al 2008]. Studies from China and Japan suggest that the spectrum of pathogenic variants may differ between Asian and European populations [Nakanishi et al 2011, Xu et al 2011].
Table 2.
USH2A Pathogenic Variants Discussed in This GeneReview
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| DNA Nucleotide Change | Predicted Protein Change | Reference Sequences |
|---|
| c.2276G>T 1 | p.Cys759Phe | NM_206933.1 2
NP_996816.1 |
| c.2299delG 1 | p.Glu767SerfsTer21 |
| c.14020A>G 1 | p.Arg4674Gly |
Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
- 1.
- 2.
Longest transcript variant of 72 exons
Normal gene product. The originally described 21 exons of USH2A (NM_007123.5) encode a protein of 1,546 amino acids. An additional 51 novel exons were subsequently identified, with the longest ORF extending from exon 2 to 72 (NM_206933.1), and encoding a putative protein of 5,202 amino acids [van Wijk et al 2004]. Expression of both the short and long isoforms is highest in the adult retina, with the long form being the most predominant, and specifically localized to the photoreceptor cells. It is also found in developing cochlear hair cells, but disappears by about postnatal day 15 [Liu et al 2007].
The short isoform (NP_009054.5) of usherin has four readily identifiable domains observed in extracellular matrix or cell adhesion proteins: a laminin G-like jellyroll fold (LamG/TSPN/PTX), also found in thrombospondins and pentraxins, laminin type VI (LN), ten laminin epidermal growth factor (LE), and four fibronectin type-III (FN3) repeats; the long isoform (NP_996816.2) has an additional 28 FN3 repeats, as well as two laminin G (LamG) domains. It is predicted to have an outside-in transmembrane region followed by an intracellular domain that includes a PDZ-binding domain at its C-terminal end [van Wijk et al 2004]. Proteins with LamG domains are involved in neuronal growth, patterning, and calcium-mediated ligand binding. The LN module of usherin has the most homology with the netrins, which are chemoattractant matrix molecules involved in nerve fiber guidance. Arrays of LE domains form rod-like tertiary structures that may provide a rigid spacer between two functional domains. FN domains in other proteins form beta-pleated sheets that bind heparin and integrin molecules. Usherin studies show colocalization with and binding to the extracellular basement membrane protein, type IV collagen, with a relatively broad tissue distribution [Bhattacharya et al 2002, Pearsall et al 2002, Bhattacharya et al 2004].
Abnormal protein product. See Molecular Genetic Pathogenesis. The Ush2a knockout mouse model has stable moderate hearing loss and develops progressive photoreceptor degeneration after age ten months [Liu et al 2007].
