Mutations in NCL Genes

Mole, SE

doi:10.1093/med/9780199590018.003.0020

Cited by 4 publications

(6 citation statements)

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“…Variant late‐onset NCL (vLINCL) is a rapidly progressing NCL with no known treatment or cure. vLINCL is known to be caused by at least 29 distinct mutations in the CLN6 gene (Mole, 2008). Currently, however, the function of CLN6 is unknown.…”

Section: Discussionmentioning

confidence: 99%

“…Through its interaction with tubulin heterodimers and the Sra‐1/WAVE1–actin complex (Kawano et al, 2005), CRMP‐2 promotes microtubule assembly (Fukata et al, 2002) and regulates cytoskeletal dynamics during axonal outgrowth and axon‐dendrite specification (Kawano et al, 2005). Mutations that cause vLINCL lead to a loss of CLN6 function, as the severity of the disease correlates with the extent of genetic mutation (Gao et al, 2002; Wheeler et al, 2002; Sharp et al, 2003; Mole, 2008), suggesting that loss of the interaction between CLN6 and CRMP‐2 may contribute to the disease pathology. To investigate the possible pathological consequences of disrupting this interaction in vLINCL, we used the nclf mouse to explore both CRMP‐2‐dependent semaphorin 3A (Sema3A)–induced axon repulsion and maturation and axon outgrowth in cultured hippocampal neurons, the classic model for examining neuronal polarization (Banker and Goslin, 1991).…”

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Protein product of CLN6 gene responsible for variant late‐onset infantile neuronal ceroid lipofuscinosis interacts with CRMP‐2

Benedict¹,

Getty²,

Wishart³

et al. 2009

J of Neuroscience Research

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Mutations in CLN6 cause variant late-onset neuronal ceroid lipofuscinosis (vLINCL), a childhood neurodegenerative disorder resulting from aberrant neuronal cell loss and pathological accumulation of lysosomal auto-fluorescent storage material in the central nervous system. The direct function of the endoplasmic reticulum– resident protein CLN6 and how dysfunction of this protein results in vLINCL are unknown. We report that CLN6 interacts with collapsin response mediator protein-2 (CRMP-2). To further understand the significance and possible contribution to vLINCL of the CLN6–CRMP-2 interaction, we utilized the nclf mouse, which harbors mutations in CLN6. Significantly, CRMP-2 protein level was found to be reduced in the nclf mouse brain, particularly in the thalamus. Because CRMP-2 functions in growth cone collapse and is an effector protein downstream of Sema3A signaling, this pathway was examined via a dorsal root ganglion (DRG) repulsion assay. However, there were no defects in the repulsion of DRGs derived from nclf mice, indicating that the loss of CLN6 does not affect Sema3A signaling. CRMP-2 has also been implicated in controlling axon number and outgrowth, as observed in cultured hippocampal neurons. Therefore, we explored the formation and maturation of hippocampal neurons derived from nclf mice in a glial coculture system. The maturation of these neurons was reduced; by day in vitro (DIV) 8, more than 50% of nclf-derived hippocampal neurons had died. Additionally, beginning around DIV4, nclf neurons were less mature than their WT counterparts, presumably because of an inability to form mature synaptic connections. We concluded that alterations in neurite maturation resulting from a loss of CLN6–CRMP-2 interaction may contribute to neuronal dysfunction and pathology in vLINCL.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Protein product of CLN6 gene responsible for variant late‐onset infantile neuronal ceroid lipofuscinosis interacts with CRMP‐2

Benedict¹,

Getty²,

Wishart³

et al. 2009

J of Neuroscience Research

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“…35 The NGS technique shows many advantages over the Sanger sequencing because it is time-saving and cost-effective, assessing multiple genes simultaneously. 36 37 When using the NGS, it is important to know whether exons and proximal intronic regions have been fully covered (consensus; LE: 5). It is also important to check if exonic deletions or duplications (also known as CNVs) were analyzed using NGS appropriate protocols, although this is not a common molecular mechanism in CLN2.…”

Section: Diagnosismentioning

confidence: 99%

Clinical management and diagnosis of CLN2 disease: consensus of the Brazilian experts group

et al. 2023

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Neuronal ceroid lipofuscinosis type 2 (CLN2) is a rare neurodegenerative genetic disease that affects children in early life. Its classic form is rapidly progressive, leading to death within the first 10 years. The urge for earlier diagnosis increases with the availability of enzyme replacement therapy. A panel of nine Brazilian child neurologists combined their expertise in CLN2 with evidence from the medical literature to establish a consensus to manage this disease in Brazil. They voted 92 questions including diagnosis, clinical manifestations, and treatment of the disease, considering the access to healthcare in this country. Clinicians should suspect CLN2 disease in any child, from 2 to 4 years old, with language delay and epilepsy. Even though the classic form is the most prevalent, atypical cases with different phenotypes can be found. Electroencephalogram, magnetic resonance imaging, molecular and biochemical testing are the main tools to investigate and confirm the diagnosis. However, we have limited access to molecular testing in Brazil, and rely on the support from the pharmaceutical industry. The management of CLN2 should involve a multidisciplinary team and focus on the quality of life of patients and on family support. Enzyme replacement therapy with Cerliponase α is an innovative treatment approved in Brazil since 2018; it delays functional decline and provides quality of life. Given the difficulties for the diagnosis and treatment of rare diseases in our public health system, the early diagnosis of CLN2 needs improvement as enzyme replacement therapy is available and modifies the prognosis of patients.

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“…Patients present with blindness between ages 5–9 preceding progressive seizures, cognitive and motor decline, schizophrenic and Parkinsonian symptoms, and eventual premature death in the second or third decade of life [1]. NCL’s are the most common pediatric neurodegenerative diseases in the world (1:12,500 live births), and JNCL is the most prevalent, resulting from autosomal recessively inherited mutations in CLN3 [2–3]. Characteristic accumulation of autofluorescent storage material in all tissues occurs; however, pathology affects the central nervous system.…”

Section: Introductionmentioning

confidence: 99%

A novel interaction of CLN3 with nonmuscle myosin-IIB and defects in cell motility of Cln3−/− cells

Getty

Benedict

Pearce

2011

Experimental Cell Research

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Juvenile neuronal ceroid lipofuscinosis (JNCL) is a pediatric lysosomal storage disorder characterized by accumulation of autofluorescent storage material and neurodegeneration, which result from mutations in CLN3. The function of CLN3, a lysosomal membrane protein, is currently unknown. We report CLN3 interacts with cytoskeleton-associated nonmuscle myosin-IIB. Both CLN3 and myosin-IIB are ubiquitously expressed, yet mutations in either produce dramatic consequences in the CNS such as neurodegeneration in JNCL patients and Cln3−/− mouse models, or developmental deficiencies in Myh10−/− mice, respectively. A scratch assay revealed a migration defect associated with Cln3−/− cells. Inhibition of nonmuscle myosin-II with blebbistatin in WT cells resulted in a phenotype that mimics the Cln3−/− migration defect. Moreover, inhibiting lysosome function by treating cells with chloroquine exacerbated the migration defect in Cln3−/−. Cln3−/− cells traversing a transwell filter under gradient trophic factor conditions displayed altered migration, further linking lysosomal function and cell migration. The myosin-IIB distribution in Cln3−/− cells is elongated, indicating a cytoskeleton defect caused by the loss of CLN3. In summary, cells lacking CLN3 have defects that suggest altered myosin-IIB activity, supporting a functional and physical interaction between CLN3 and myosin-IIB. We propose the migration defect in Cln3−/− results, in part, from the loss of the CLN3-myosin-IIB interaction.

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Mutations in NCL Genes

Cited by 4 publications

References 0 publications

Protein product of CLN6 gene responsible for variant late‐onset infantile neuronal ceroid lipofuscinosis interacts with CRMP‐2

Protein product of CLN6 gene responsible for variant late‐onset infantile neuronal ceroid lipofuscinosis interacts with CRMP‐2

Clinical management and diagnosis of CLN2 disease: consensus of the Brazilian experts group

A novel interaction of CLN3 with nonmuscle myosin-IIB and defects in cell motility of Cln3−/− cells

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