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A mutation in Myo15 leads to Usher-like symptoms in LEW/Ztm-ci2 rats.

Held N, Smits BM, Gockeln R, Schubert S, Nave H, Northrup E, Cuppen E, Hedrich HJ, Wedekind D - PLoS ONE (2011)

Bottom Line: Interestingly, the manifestation of the disease does not solely depend on the mutation, but also on environmental factors.Since the LEW/Ztm-ci2 rat features the entire range of symptoms of the human Usher syndrome we think that this strain is an appropriate model for this disease.Our findings display that mutations in binding domains of myosin XV do not only cause non-syndromic hearing loss but can also lead to syndromic disorders including retinal dysfunction.

View Article: PubMed Central - PubMed

Affiliation: Institute of Laboratory Animal Science, Hannover Medical School, Hannover, Germany.

ABSTRACT
The LEW/Ztm-ci2 rat is an animal model for syndromal deafness that arose from a spontaneous mutation. Homozygous animals show locomotor abnormalities like lateralized circling behavior. Additionally, an impaired vision can be observed in some animals through behavioral studies. Syndromal deafness as well as retinal degeneration are features of the Usher syndrome in humans. In the present study, the mutation was identified as a base substitution (T->C) in exon 56 of Myo15, leading to an amino acid exchange from leucine (Leu) to proline (Pro) within the carboxy-terminal MyTH4 domain in the proteins' tail region. Myo15 mRNA was expressed in the retina as demonstrated for the first time with the help of in-situ hybridization and PCR. To characterize the visual phenotype, rats were examined by scotopic and photopic electroretinography and, additionally, histological analyses of the retinas were conducted. The complete loss of sight was detected along with a severe degeneration of photoreceptor cells. Interestingly, the manifestation of the disease does not solely depend on the mutation, but also on environmental factors. Since the LEW/Ztm-ci2 rat features the entire range of symptoms of the human Usher syndrome we think that this strain is an appropriate model for this disease. Our findings display that mutations in binding domains of myosin XV do not only cause non-syndromic hearing loss but can also lead to syndromic disorders including retinal dysfunction.

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Histological examinations of retinae from unaffected and affected LEW/Ztm-ci2 rats.(A.) Unaffected LEW/Ztm-ci2 rat (MedSchool group) showing slight reduction of photoreceptor cells due to age (B.) Affected LEW/Ztm-ci2 rat (VetSchool group) with distinct reduction of number and density of rod and cone somata within the ONL (C.) Severely affected LEW/Ztm-ci2 rat (VetSchool group) cell bodies, inner and outer segments of photoreceptor cells are nearly absent while the remaining retinal layers are arranged in a normal pattern (×400) NF = Nerve fibres, IPL = Inner Plexiform Layer, INL = Inner Nuclear Layer, OPL = Outer Plexiform Layer, ONL = Outer Nuclear Layer, PRC = Inner and Outer Segments of Photoreceptor Cells, RPE = Retinal Pigment Epithelium.
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pone-0015669-g004: Histological examinations of retinae from unaffected and affected LEW/Ztm-ci2 rats.(A.) Unaffected LEW/Ztm-ci2 rat (MedSchool group) showing slight reduction of photoreceptor cells due to age (B.) Affected LEW/Ztm-ci2 rat (VetSchool group) with distinct reduction of number and density of rod and cone somata within the ONL (C.) Severely affected LEW/Ztm-ci2 rat (VetSchool group) cell bodies, inner and outer segments of photoreceptor cells are nearly absent while the remaining retinal layers are arranged in a normal pattern (×400) NF = Nerve fibres, IPL = Inner Plexiform Layer, INL = Inner Nuclear Layer, OPL = Outer Plexiform Layer, ONL = Outer Nuclear Layer, PRC = Inner and Outer Segments of Photoreceptor Cells, RPE = Retinal Pigment Epithelium.

Mentions: Electroretinography is an appropriate method for the early detection of retinal alterations as morphological changes usually do not appear until ERG responses are dramatically reduced. Due to the strong reduction of photoreceptor responses in LEW/Ztm-ci2 animals of the VetSchool group we examined the eyes histologically. Three eyes of LEW/Ztm-ci2 rats and LEW/Ztm rats were looked at per group (MedSchool, VetSchool), 12 samples in total. All samples in LEW/Ztm-ci2 rats from the VetSchool group showed some degree of pathological alteration ranging from a diminution to a complete loss of the photoreceptor cell layer and the outer nuclear layer (Fig. 4-B/C). Interestingly, the remaining cell layers (inner nuclear layer, inner and outer plexiform layers) and the retinal pigment epithelium appeared intact. In contrast, none of the LEW/Ztm-ci2 and LEW/Ztm rats of the MedSchool group showed any signs of photoreceptor degeneration (Fig. 4-A).


A mutation in Myo15 leads to Usher-like symptoms in LEW/Ztm-ci2 rats.

Held N, Smits BM, Gockeln R, Schubert S, Nave H, Northrup E, Cuppen E, Hedrich HJ, Wedekind D - PLoS ONE (2011)

Histological examinations of retinae from unaffected and affected LEW/Ztm-ci2 rats.(A.) Unaffected LEW/Ztm-ci2 rat (MedSchool group) showing slight reduction of photoreceptor cells due to age (B.) Affected LEW/Ztm-ci2 rat (VetSchool group) with distinct reduction of number and density of rod and cone somata within the ONL (C.) Severely affected LEW/Ztm-ci2 rat (VetSchool group) cell bodies, inner and outer segments of photoreceptor cells are nearly absent while the remaining retinal layers are arranged in a normal pattern (×400) NF = Nerve fibres, IPL = Inner Plexiform Layer, INL = Inner Nuclear Layer, OPL = Outer Plexiform Layer, ONL = Outer Nuclear Layer, PRC = Inner and Outer Segments of Photoreceptor Cells, RPE = Retinal Pigment Epithelium.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3066203&req=5

pone-0015669-g004: Histological examinations of retinae from unaffected and affected LEW/Ztm-ci2 rats.(A.) Unaffected LEW/Ztm-ci2 rat (MedSchool group) showing slight reduction of photoreceptor cells due to age (B.) Affected LEW/Ztm-ci2 rat (VetSchool group) with distinct reduction of number and density of rod and cone somata within the ONL (C.) Severely affected LEW/Ztm-ci2 rat (VetSchool group) cell bodies, inner and outer segments of photoreceptor cells are nearly absent while the remaining retinal layers are arranged in a normal pattern (×400) NF = Nerve fibres, IPL = Inner Plexiform Layer, INL = Inner Nuclear Layer, OPL = Outer Plexiform Layer, ONL = Outer Nuclear Layer, PRC = Inner and Outer Segments of Photoreceptor Cells, RPE = Retinal Pigment Epithelium.
Mentions: Electroretinography is an appropriate method for the early detection of retinal alterations as morphological changes usually do not appear until ERG responses are dramatically reduced. Due to the strong reduction of photoreceptor responses in LEW/Ztm-ci2 animals of the VetSchool group we examined the eyes histologically. Three eyes of LEW/Ztm-ci2 rats and LEW/Ztm rats were looked at per group (MedSchool, VetSchool), 12 samples in total. All samples in LEW/Ztm-ci2 rats from the VetSchool group showed some degree of pathological alteration ranging from a diminution to a complete loss of the photoreceptor cell layer and the outer nuclear layer (Fig. 4-B/C). Interestingly, the remaining cell layers (inner nuclear layer, inner and outer plexiform layers) and the retinal pigment epithelium appeared intact. In contrast, none of the LEW/Ztm-ci2 and LEW/Ztm rats of the MedSchool group showed any signs of photoreceptor degeneration (Fig. 4-A).

Bottom Line: Interestingly, the manifestation of the disease does not solely depend on the mutation, but also on environmental factors.Since the LEW/Ztm-ci2 rat features the entire range of symptoms of the human Usher syndrome we think that this strain is an appropriate model for this disease.Our findings display that mutations in binding domains of myosin XV do not only cause non-syndromic hearing loss but can also lead to syndromic disorders including retinal dysfunction.

View Article: PubMed Central - PubMed

Affiliation: Institute of Laboratory Animal Science, Hannover Medical School, Hannover, Germany.

ABSTRACT
The LEW/Ztm-ci2 rat is an animal model for syndromal deafness that arose from a spontaneous mutation. Homozygous animals show locomotor abnormalities like lateralized circling behavior. Additionally, an impaired vision can be observed in some animals through behavioral studies. Syndromal deafness as well as retinal degeneration are features of the Usher syndrome in humans. In the present study, the mutation was identified as a base substitution (T->C) in exon 56 of Myo15, leading to an amino acid exchange from leucine (Leu) to proline (Pro) within the carboxy-terminal MyTH4 domain in the proteins' tail region. Myo15 mRNA was expressed in the retina as demonstrated for the first time with the help of in-situ hybridization and PCR. To characterize the visual phenotype, rats were examined by scotopic and photopic electroretinography and, additionally, histological analyses of the retinas were conducted. The complete loss of sight was detected along with a severe degeneration of photoreceptor cells. Interestingly, the manifestation of the disease does not solely depend on the mutation, but also on environmental factors. Since the LEW/Ztm-ci2 rat features the entire range of symptoms of the human Usher syndrome we think that this strain is an appropriate model for this disease. Our findings display that mutations in binding domains of myosin XV do not only cause non-syndromic hearing loss but can also lead to syndromic disorders including retinal dysfunction.

Show MeSH
Related in: MedlinePlus