Mice homozygous for c.451C&gt;T mutation in <i>Cln1</i> gene recapitulate <scp>INCL</scp> phenotype

Bouchelion, Ashleigh; Zhang, Zhongjian; Li, Yichao; Qian, Haohua; Mukherjee, Anil B.

doi:10.1002/acn3.144

Cited by 26 publications

(32 citation statements)

References 41 publications

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“…Deletion of exon 4 replicates infantile NCL, and homozygous mutant mice show loss of vision from 8 weeks of age, seizures after 4 months and paralysis of hind limbs starting at 5 months (Jalanko et al 2005). Mice with an inserted premature stop codon in exon 5 show hindlimb spasticity and granular osmiophilic deposits in brain and spleen, along with retinal degeneration (Bouchelion et al 2014). Similarly, PPT1 genetic variants in dog are also associated with neurologic abnormalities and blindness.…”

Section: Discussionmentioning

confidence: 99%

Complex Structural PPT1 Variant Associated with Non-syndromic Canine Retinal Degeneration

Murgiano

Becker

Torjman

et al. 2019

G3 Genes|Genomes|Genetics

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Rod and cone photoreceptors are specialized retinal neurons that have a fundamental role in visual perception, capturing light and transducing it into a neuronal signal. Aberrant functioning of rod and/or cone photoreceptors can ultimately lead to progressive degeneration and eventually blindness. In man, many rod and rod-cone degenerative diseases are classified as forms of retinitis pigmentosa (RP). Dogs also have a comparable disease grouping termed progressive retinal atrophy (PRA). These diseases are generally due to single gene defects and follow Mendelian inheritance.We collected 51 DNA samples from Miniature Schnauzers affected by PRA (average age of diagnosis ∼3.9 ±1 years), as well as from 56 clinically normal controls of the same breed (average age ∼6.6 ±2.8 years). Pedigree analysis suggested monogenic autosomal recessive inheritance of PRA. GWAS and homozygosity mapping defined a critical interval in the first 4,796,806 bp of CFA15. Whole genome sequencing of two affected cases, a carrier and a control identified two candidate variants within the critical interval. One was an intronic SNV in HIVEP3 , and the other was a complex structural variant consisting of the duplication of exon 5 of the PPT1 gene along with a conversion and insertion (named PPT1 dci ). PPT1 dci was confirmed homozygous in a cohort of 22 cases, and 12 more cases were homozygous for the CFA15 haplotype. Additionally, the variant was found homozygous in 6 non-affected dogs of age higher than the average age of onset. The HIVEP3 variant was found heterozygous (n = 4) and homozygous wild-type (n = 1) in cases either homozygous for PPT1 dci or for the mapped CFA15 haplotype. We detected the wildtype and three aberrant PPT1 transcripts in isolated white blood cell mRNA extracted from a PRA case homozygous for PPT1 dci , and the aberrant transcripts involved inclusion of the duplicated exon 5 and novel exons following the activation of cryptic splice sites. No neurological signs were detected among the dogs homozygous for the PPT1 dci variant. Therefore, we propose PPT1 dci as causative for a non-syndromic form of PRA (PRA PPT1 ) that shows incomplete penetrance in Miniature Schnauzers, potentially related to the presence of the wild-type transcript. To our knowledge, this is the first case of isolated retinal degeneration associated with a PPT1 variant.

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Section: Discussionmentioning

confidence: 99%

Complex Structural PPT1 Variant Associated with Non-syndromic Canine Retinal Degeneration

Murgiano

Becker

Torjman

et al. 2019

G3 Genes|Genomes|Genetics

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“…In Cln1 −/− mice 33 that recapitulate virtually all clinical pathological features of INCL 34 neuronal death is followed by infiltration of activated astrocytes and microglia. Recently, we generated another mouse model of INCL 35 by knocking-in the Cln1 nonsense mutation (c.451C>T) most commonly found in the US INCL patient population. These mice also showed infiltration of activated astrocytes and microglia in the brain, which followed neuronal death.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of disease progression in INCL by MR spectroscopy

Baker

Levin

Zhang

et al. 2015

Ann Clin Transl Neurol

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ObjectiveInfantile neuronal ceroid lipofuscinosis (INCL) is a devastating neurodegenerative storage disease caused by palmitoyl-protein thioesterase-1 deficiency, which impairs degradation of palmitoylated proteins (constituents of ceroid) by lysosomal hydrolases. Consequent lysosomal ceroid accumulation leads to neuronal injury. As part of a pilot study to evaluate treatment benefits of cysteamine bitartrate and N-acetylcysteine, we quantitatively measured brain metabolite levels using magnetic resonance spectroscopy (MRS).MethodsA subset of two patients from a larger treatment and follow-up study underwent serial quantitative single-voxel MRS examinations of five anatomical sites. Three echo times were acquired in order to estimate metabolite T2. Measured metabolite levels included correction for partial volume of cerebrospinal fluid. Comparison of INCL patients was made to a reference group composed of asymptomatic and minimally symptomatic Niemann-Pick disease type C patients.ResultsIn INCL patients, N-acetylaspartate (NAA) was abnormally low at all locations upon initial measurement, and further declined throughout the follow-up period. In the cerebrum (affected early in the disease course), choline and myo-inositol were initially elevated and fell during the follow-up period, whereas in the cerebellum and brainstem (affected later), choline and myo-inositol were initially normal and rose subsequently.InterpretationCholine and myo-inositol levels in our patients are consistent with patterns of neuroinflammation observed in two INCL mouse models. Low, persistently declining NAA was expected based on the progressive, irreversible nature of the disease. Progression of metabolite levels in INCL has not been previously quantified; therefore the results of this study serve as a reference for quantitative evaluation of future therapeutic interventions.

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“…However, this treatment yielded only a very modest increase in Ppt1 enzyme activity [212]. This study was followed by the generation of two Cln1 -knock-in (KI) mouse models carrying a lethal nonsense mutation in the Cln1 gene commonly found in INCL patients in the US [213, 214]. In one study [213], PTC124 was tested in vivo using Ppt1-KI mice, which yielded promising results.…”

Section: Introductionmentioning

confidence: 99%

Emerging new roles of the lysosome and neuronal ceroid lipofuscinoses

Mukherjee

Appu

Sadhukhan

et al. 2019

Mol Neurodegeneration

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Neuronal Ceroid Lipofuscinoses (NCLs), commonly known as Batten disease, constitute a group of the most prevalent neurodegenerative lysosomal storage disorders (LSDs). Mutations in at least 13 different genes (called CLNs) cause various forms of NCLs. Clinically, the NCLs manifest early impairment of vision, progressive decline in cognitive and motor functions, seizures and a shortened lifespan. At the cellular level, all NCLs show intracellular accumulation of autofluorescent material (called ceroid) and progressive neuron loss. Despite intense studies the normal physiological functions of each of the CLN genes remain poorly understood. Consequently, the development of mechanism-based therapeutic strategies remains challenging. Endolysosomal dysfunction contributes to pathogenesis of virtually all LSDs. Studies within the past decade have drastically changed the notion that the lysosomes are merely the terminal degradative organelles. The emerging new roles of the lysosome include its central role in nutrient-dependent signal transduction regulating metabolism and cellular proliferation or quiescence. In this review, we first provide a brief overview of the endolysosomal and autophagic pathways, lysosomal acidification and endosome-lysosome and autophagosome-lysosome fusions. We emphasize the importance of these processes as their dysregulation leads to pathogenesis of many LSDs including the NCLs. We also describe what is currently known about each of the 13 CLN genes and their products and how understanding the emerging new roles of the lysosome may clarify the underlying pathogenic mechanisms of the NCLs. Finally, we discuss the current and emerging therapeutic strategies for various NCLs.

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Mice homozygous for c.451C>T mutation in Cln1 gene recapitulate INCL phenotype

Cited by 26 publications

References 41 publications

Complex Structural PPT1 Variant Associated with Non-syndromic Canine Retinal Degeneration

Complex Structural PPT1 Variant Associated with Non-syndromic Canine Retinal Degeneration

Evaluation of disease progression in INCL by MR spectroscopy

Emerging new roles of the lysosome and neuronal ceroid lipofuscinoses

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