Clinical findings in obligate carriers of type I Usher syndrome

Wagenaar, M.; Rahe, B. ter; Aarem, A. van; Huygen, P.L.M.; Admiraal, R.J.C.; Bleeker‐Wagemakers, E. M.; Pinckers, A.; Kimberling, William J.; Cremers, C.W.R.J.

doi:10.1002/ajmg.1320590319

Cited by 13 publications

(5 citation statements)

References 23 publications

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“…As well as delineating the region containing the gene, these closely linked markers provide data for determining if a relative of an affected member is a carrier, and for an endogamous population such as the Acadians the marker information can be used to calculate the probability that any member of the population is a carrier. Some studies suggest that audiometric and electrooculographic analyses may also be helpful for detecting carriers, although results are inconclusive [van Aarem et al, 1995b;Meredith et al, 1992;Wagenaar et al, 1995Wagenaar et al, , 1996. However, detailed otoacoustic emission testing of Ashkenazi Jewish carriers of the 167delT mutation in the connexin-26 gene (GJB2) suggested differences in emission patterns between those who carry the mutation and those who do not ].…”

Section: Discussionmentioning

confidence: 99%

The Usher syndromes

Keats

Corey²

1999

Am. J. Med. Genet.

138

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Mutations in the gene (MYO7A) encoding myosin-VIIa, a member of the large superfamily of myosin motor proteins that move on cytoplasmic actin filaments, and in the USH2A gene, which encodes a novel protein resembling an extracellular matrix protein or a cell adhesion molecule, both cause Usher syndrome (USH), a clinically heterogeneous autosomal recessive disorder comprising hearing and visual impairment. Patients with USH1 have severe to profound congenital hearing impairment, vestibular dysfunction, and retinal degeneration beginning in childhood, while those with USH2 have moderate to severe hearing impairment, normal vestibular function, and later onset of retinal degeneration. USH3 is characterized by progressive hearing loss and variable age of onset of retinal degeneration. The phenotype resulting from MYO7A and USH2A mutations is variable. While most MYO7A mutations cause USH1, some cause nonsyndromic hearing impairment, and one USH3 phenotype has been described. USH2A mutations cause atypical USH as well as USH2. MYO7A is on chromosome region 11q13 and USH2A is on 1q41. Seven other USH genes have been mapped but have not yet been identified. USH1A, USH1C, USH1D, USH1E, and USH1F have been assigned to chromosome bands 14q32, 11p15.1, 10q, 21q21, and 10, respectively, while USH2B is on 5q, and USH3 is at 3q21-q25. Myosin VIIa mutations also result in the shaker-1 (sh1) mouse, providing a model for functional studies. One possibility is that myosin-VIIa is required for linking stereocilia in the sensory hair bundle; another is that it may be needed for membrane trafficking. The ongoing studies of myosin-VIIa, the USH2A protein, and the yet to be identified proteins encoded by the other USH genes will advance understanding of the Usher syndromes and contribute to the development of effective therapies. Am. J. Med. Genet. (Semin. Med. Genet.) 89:158-166, 1999.

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Section: Discussionmentioning

confidence: 99%

The Usher syndromes

Keats

Corey²

1999

Am. J. Med. Genet.

138

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“…The discrepancies may be due, at least in part, to the various criteria for classifying the Usher types [2, 34, 35, 36, 37]. A higher frequency of USII was observed in our sample because most of the Usher families were drawn from the RP Association of the Valencian Community.…”

Section: Discussionmentioning

confidence: 72%

Epidemiology of Usher Syndrome in Valencia and Spain

Espinós

Millán²,

Beneyto³

et al. 1998

Public Health Genomics

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Objective: To obtain epidemiological data on the prevalence of the different types of Usher syndrome (US) in Spain, since these data were missing; to estimate the proportion of sporadic cases among simplex families, and calculate the prevalence of the Usher syndrome in a homogeneous population from Eastern Spain (3,875,234 inhabitants) that is representative of the Spanish population. Methods: Otological, ophthalmological and genetic studies were performed in 89 US patients from 46 families and subjected to statistical and segregation analysis. Results: 41.6% of them suffered US type I, 46.1% type II, and in 12.3% the classification remains unclear. The estimated prevalence for the Province of Valencia was 4.2/100,000. There was a notable excess of male-only affected multiplex sibships in our sample that could be attributable to an X-linked inheritance. Conclusions: The number of families with USI type was similar to that of families with USII type. The estimated prevalence for the Province of Valencia is in agreement with other reports in which the estimate for the prevalence of US ranges from 1.8 to 6.2/100,000.

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“…These findings were associated with Usher’s syndrome as a whole, however, because genetic linkage had not yet been established. By the 1990s, USH1B had been linked to chromosome region 11p13-15 (Kimberling et al, 1992; Smith et al, 1992; Bonnetamir et al, 1994; Weil et al, 1995) and studies found that a number of obligate carriers exhibited significant audiological and ophthalmological abnormalities (Wagenaar et al, 1995). These clinical findings are intriguing, and align with our findings in heterozygous Myo7a +/– mice, but a more comprehensive assessment of genetically confirmed USH1B carriers is warranted to determine their significance.…”

Section: Discussionmentioning

confidence: 99%

A Novel Mouse Model of MYO7A USH1B Reveals Auditory and Visual System Haploinsufficiencies

et al. 2019

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Usher’s syndrome is the most common combined blindness–deafness disorder with USH1B, caused by mutations in MYO7A, resulting in the most severe phenotype. The existence of numerous, naturally occurring shaker1 mice harboring variable MYO7A mutations on different genetic backgrounds has complicated the characterization of MYO7A knockout (KO) and heterozygote mice. We generated a novel MYO7A KO mouse (Myo7a–/–) that is easily genotyped, maintained, and confirmed to be null for MYO7A in both the eye and inner ear. Like USH1B patients, Myo7a–/– mice are profoundly deaf, and display near complete loss of inner and outer cochlear hair cells (HCs). No gross structural changes were observed in vestibular HCs. Myo7a–/– mice exhibited modest declines in retinal function but, unlike patients, no loss of retinal structure. We attribute the latter to differential expression of MYO7A in mouse vs. primate retina. Interestingly, heterozygous Myo7a+/– mice had reduced numbers of cochlear HCs and concomitant reductions in auditory function relative to Myo7a+/+ controls. Notably, this is the first report that loss of a single Myo7a allele significantly alters auditory structure and function and suggests that audiological characterization of USH1B carriers is warranted. Maintenance of vestibular HCs in Myo7a–/– mice suggests that gene replacement could be used to correct the vestibular dysfunction in USH1B patients. While Myo7a–/– mice do not exhibit sufficiently robust retinal phenotypes to be used as a therapeutic outcome measure, they can be used to assess expression of vectored MYO7A on a null background and generate valuable pre-clinical data toward the treatment of USH1B.

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Clinical findings in obligate carriers of type I Usher syndrome

Cited by 13 publications

References 23 publications

The Usher syndromes

The Usher syndromes

Epidemiology of Usher Syndrome in Valencia and Spain

A Novel Mouse Model of MYO7A USH1B Reveals Auditory and Visual System Haploinsufficiencies

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