Expanded Phenotype of the <i>Cln6<sup>nclf</sup></i> Mouse Model
Neuronal ceroid lipofuscinoses (NCLs) are a group of autosomal recessive neurogenetic disorders caused by mutations in 14 different genes. CLN6 disease manifests as variant late-infantile NCL (vLINCL) or as an adult variant. In childhood, symptoms include speech delay, vision loss, cognitive and mot...
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| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-04-01
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| Series: | Cells |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2073-4409/14/9/661 |
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| Summary: | Neuronal ceroid lipofuscinoses (NCLs) are a group of autosomal recessive neurogenetic disorders caused by mutations in 14 different genes. CLN6 disease manifests as variant late-infantile NCL (vLINCL) or as an adult variant. In childhood, symptoms include speech delay, vision loss, cognitive and motor decline, seizures, and early death. An in-depth characterization of a naturally occurring Cln6 mutant mouse (<i>Cln6<sup>nclf</sup></i>) is presented, with implications for translational research. The expanded phenotype provides data showing early death, vision loss, and motor deficits in male and female <i>Cln6<sup>nclf</sup></i> mice. Diminished visual acuity in <i>Cln6<sup>nclf</sup></i> mice was noted at 28 weeks of age, but the pathological loss of retinal layers began as early as 2 weeks or postnatal day 14 (P14). Apoptosis was confirmed by TUNEL staining in the <i>Cln6<sup>nclf</sup></i> mouse brain at P8 and in the retina at P12. A peak in glial fibrillary acidic protein (GFAP) expression was established as a normal developmental phenomenon in the wild-type and <i>Cln6<sup>nclf</sup></i> mouse brain cerebellum and the CA2–CA3 regions of the hippocampus at P8. In <i>Cln6<sup>nclf</sup></i> mice, GFAP levels were elevated at P12 in the cerebellum and hippocampus. In the retina, a developmental peak in gliosis was absent, with increased astrogliosis noted at P6 and P8 in female and male <i>Cln6<sup>nclf</sup></i> mice, respectively. This highlights the lack of a sex-dependent response in wild-type mice. These novel data position the <i>Cln6<sup>nclf</sup></i> mouse model as a useful tool for screening potential therapeutics for human CLN6 disease. |
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| ISSN: | 2073-4409 |