Usher Syndrome, Type If

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Retrieved

2019-09-22

Source

Omim

Trials

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Genes

MYO7A, PCDH15, HARS1, PLD4, USH1C, ADGRV1, USH2A, CDH23, CEP250, ARSG, PROM1, CLRN1, ZDHHC24, CDH23-AS1, TRNS2, BBS1, GUCA1A, WHRN, USH1G, PDZD7, CIB2, GJB2, ESPN, HTC2, GC, CEP78, ABHD12, PCARE, GPR166P, LGR6, INTS2, VN1R17P, MRGPRX1, FADS6, MRGPRX3, MRGPRX4, ASIC5, GPR151, OXER1, LCA5, GPRC6A, VEZT, ACTB, MYO15A, PRPH2, ENG, FGF3, GBX2, MEF2C, MYO5B, NOTCH2, NUCB2, OMP, PEX6, RCVRN, RPGR, PHPT1, SOX3, STATH, USH1E, WFS1, FZD4, OTOF, CIB1, ASAH1, NINL, LPAR3, IMMT

Drugs

Adeno-associated virus serotype 8 containing the human RdCVF sequence and the human RdCVFL sequence, Combination of three adeno-associated viral vectors of serotype 8 containing the 5'-, the body- and the 3'- coding sequences of human CEP290 fused to inteins, Lentiviral vector containing the human MYO7A gene, Mixture of two adeno-associated viral vectors serotype 8 containing the 5'-half sequence of human MYO7A gene and the 3'-half sequence of human MYO7A gene

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A number sign (#) is used with this entry because Usher syndrome type IF (USH1F) can be caused by homozygous or compound heterozygous mutation in the protocadherin-15 gene (PCDH15; 605514) on chromosome 10q.

See 601067 for a form of Usher syndrome type I (USH1D/F) caused by digenic mutation in the CDH23 (605516) and PCDH15 genes.

For a general description and a discussion of genetic heterogeneity of USH1, see 276900.

Description

Usher syndrome constitutes a group of autosomal recessive disorders characterized by progressive pigmentary retinopathy and sensorineural hearing loss. Phenotypic distinctions are based on auditory and vestibular differences. Persons with forms of Usher syndrome type I (276900) have congenital severe to profound hearing loss and vestibular dysfunction.

Mapping

Wayne et al. (1997) noted that known localizations of USH forms accounted for approximately 90% of clinical cases of USH. They stated that at least 2 additional USH genes must exist because a few families with USH1 did not map to any of the known loci, and nearly 10% of USH2 families had been excluded from 1q. Studying an inbred Hutterite family with 2 persons affected with USH1, Wayne et al. (1997) identified a new USH1 locus by homozygosity mapping. After excluding linkage to known USH loci, 2 genomic DNA pools, one from the affected individuals and the other from the unaffected individuals, were used to screen 153 polymorphic markers evenly spaced across the autosomal human genome. A 15-cM interval of homozygosity by descent bounded by D10S199 and D10S596 was found in the affected individuals. A lod score of 3.06 was calculated from individual genotyping data.

Ahmed et al. (2001) refined the map location of USH1F to an interval of 1 Mb of genomic DNA at chromosome 10q21.1.

Molecular Genetics

In 2 Pakistani families segregating Usher syndrome type 1F, Ahmed et al. (2001) demonstrated 2 homozygous mutations (IVS27-2A-G, 605514.0001; and arg3 to ter, 605514.0002) in the protocadherin-15 gene (PCDH15; 605514).

In cell culture studies, Rebibo-Sabbah et al. (2007) demonstrated that aminoglycosides suppressed translation of several PCDH15 nonsense mutations identified in patients with Usher syndrome type 1F. The aminoglycosides resulted in variable full-length protein levels resulting from partial read-through of the nonsense mutations. Rebibo-Sabbah et al. (2007) postulated that such treatment could potentially delay the progression of retinitis pigmentosa in patients with the disorder.

Ahmed et al. (2008) identified mutations in the PCDH15 gene in 7 of 12 consanguineous Pakistani families with USH1F. Six mutations were novel (see, e.g., 605514.0009). The remaining 5 families showed linkage to chromosome 10q21, but no pathogenic mutations in the PCDH15 gene were identified.

Animal Model

Chance et al. (2010) identified proteins and protein networks associated with cochlear pathogenesis in the Ames waltzer mouse, a model for deafness in USH1F. Cochlear protein from wildtype and Ames waltzer mice at postnatal day 30, a time point in which cochlear pathology is well established, was analyzed by quantitative 2D gel electrophoresis followed by mass spectrometry (MS). Of 2,270 spots, 69 spots showed significant changes in intensity in the Ames waltzer cochlea compared with the control. The cochlin (COCH; 603196) protein was identified in 20 peptide spots; most of which were upregulated, whereas a few were downregulated. Analysis of MS sequence data showed that, in the Ames waltzer cochlea, a set of full-length isoforms of cochlin was upregulated, whereas isoforms missing the N-terminal FCH/LCCL domain were downregulated. Protein interaction network analysis of all differentially expressed proteins revealed a number of statistically significant candidate protein networks predicted to be altered in the affected cochlea. Quantitative PCR (qPCR) analysis of select candidates from the proteomic and bioinformatic investigations showed upregulation of Coch mRNA and those of p53 (191170), Brn3a (POU4F1; 601632), and Nrf2 (NFE2L2; 600492), transcription factors linked to stress response and survival. Chance et al. (2010) suggested that an increased level of cochlin may be an important etiologic factor leading to the degeneration of cochlear neuroepithelia in the USH1F model.