NCLs and ER: A stressful relationship

Marotta, Davide; Tinelli, Elisa; Mole, Sara

doi:10.1016/j.bbadis.2017.04.003

Cited by 22 publications

(35 citation statements)

References 107 publications

(143 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…ER plays a critical role for normal cell function. Alteration of ER homeostasis can lead accumulation of misfolded protein and activate the unfolded protein response to induce some diseases [ 13 ]. The abnormalities of ER caused by CLN6 mutations may decrease ER homeostasis and then affect lysosomal function.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

A first CLN6 variant case of late infantile neuronal ceroid lipofuscinosis caused by a homozygous mutation in a boy from China: a case report

et al. 2018

View full text Add to dashboard Cite

BackgroundNeuronal ceroid lipofuscinosis (NCLs) are lysosomal storage disorders characterized by seizures, motor impairment, and loss of vision. Ceroid lipofuscinosis (CLN) gene mutations are the cause, but NCL cases arising from CLN6 mutations have not been described in China to date. The CLN6 protein, which plays a role in lysosomal function, is an endoplasmic reticulum (ER) membrane protein with seven transmembrane (TM) domains. It has a cytosolic-facing amino terminal domain and a luminal-facing carboxyl terminal domain, with six loops between the TM domains.Case presentationHere we report a case involving a Chinese boy whose suspected diagnosis was a hereditary leukoencephalopathy, based on brain MRI imaging and epilepsy symptoms, language articulation disorders, ataxia, and unstable gait. The electroencephalogram showed epileptic discharges, and the brain MRI scan showed high signal intensity adjacent to the bilateral posterior horns of the lateral ventricles on T2-weighted images, along with cerebellar atrophy. Using next-generation sequencing for the genes in a panel for hereditary leukoencephalopathies, we detected a homozygous missense point mutation c.892G > A(p.Glu298Lys) in CLN6, and the variant was interpreted as pathogenic on in silico analysis. Absence of this mutation was confirmed in 259 controls. Late infantile NCL and secondary epilepsy were diagnosed, and oral sodium valproate was prescribed. The epilepsy was not well controlled, however, and the other signs had not improved at the 6-month follow-up. We also analyzed the loci of 31 CLN6 missense mutations, including those previously reported and the current one. We found that 22.6% (7/31) of the mutations are in the cytoplasmic domains, about 32.2% (10/31) are in the TM domains, and about 45.2% (14/31) are in the luminal domains. These mutations were mostly located in the TM3-TM4 loop (6/31), TM1-TM2 loop (4/31), and C-terminus (4/31), with none found in the TM4-TM5 loop, TM5-TM6 loop, or TM7.ConclusionsWe report the first case in China of NCL caused by a CLN6 mutation, expanding the genotype options for NCLs. In practice, NCLs generally are not the initial suspected diagnosis for such cases. Use of a gene sequencing panel for investigating unexplained seizures or leukoencephalopathies can help confirm the diagnosis.Electronic supplementary materialThe online version of this article (10.1186/s12881-018-0690-x) contains supplementary material, which is available to authorized users.

show abstract

Section: Discussionmentioning

confidence: 99%

“…The abnormalities of ER caused by CLN6 mutations may decrease ER homeostasis and then affect lysosomal function. Increased biometal levels such as zinc and copper have been observed in CLN6 disease, and biometal dyshomeostasis can interfere with protein folding and cause activation of ER stress with subsequent neuron apoptosis [ 13 ].…”

Section: Discussionmentioning

confidence: 99%

A first CLN6 variant case of late infantile neuronal ceroid lipofuscinosis caused by a homozygous mutation in a boy from China: a case report

et al. 2018

View full text Add to dashboard Cite

show abstract

“…A unified hypothesis explaining the mechanistic association between mutations in lysosomal genes and PD is currently lacking. While we favor the loss-of-function paradigm, the appearance of endoplasmic reticulum stress and of the unfolded protein response in some LSDs [ 48 , 49 , 50 , 51 , 52 ] and in PD [ 53 , 54 , 55 , 56 ] lends some credence to the gain-of-function hypothesis ( Figure 1 , pathway B). In reality, both loss and gain of function probably contribute to the association between the lysosome and PD.…”

Section: Lysosomal Dysfunction and Pdmentioning

confidence: 78%

Lysosomal Storage Disorders Shed Light on Lysosomal Dysfunction in Parkinson’s Disease

Blumenreich

Barav

Jenkins

et al. 2020

IJMS

View full text Add to dashboard Cite

The lysosome is a central player in the cell, acting as a clearing house for macromolecular degradation, but also plays a critical role in a variety of additional metabolic and regulatory processes. The lysosome has recently attracted the attention of neurobiologists and neurologists since a number of neurological diseases involve a lysosomal component. Among these is Parkinson’s disease (PD). While heterozygous and homozygous mutations in GBA1 are the highest genetic risk factor for PD, studies performed over the past decade have suggested that lysosomal loss of function is likely involved in PD pathology, since a significant percent of PD patients have a mutation in one or more genes that cause a lysosomal storage disease (LSD). Although the mechanistic connection between the lysosome and PD remains somewhat enigmatic, significant evidence is accumulating that lysosomal dysfunction plays a central role in PD pathophysiology. Thus, lysosomal dysfunction, resulting from mutations in lysosomal genes, may enhance the accumulation of α-synuclein in the brain, which may result in the earlier development of PD.

show abstract

“…While the NCLs are clinically stratified by their causative gene mutation, outlined previously in this review and in the table below, their aetiological diversity appears to converge upon a spectrum of common clinical phenotypes. It is therefore likely that the molecular origins underpinning the individual NCLs also converge upon common pathological cascades, resulting in unifying cellular pathogeneses including defects in lysosomal function, mitochondrial dysfunction, and alterations in the endoplasmic reticulum and endo-lysosomal trafficking [9][10][11]. Table 1 highlights some recent studies incorporating these Omics technologies and some of the exciting findings from these studies will be discussed in more detail below.…”

Section: Why Apply Omics Technologies To the Neuronal Ceroid Lipofuscmentioning

confidence: 99%

Applying modern Omic technologies to the Neuronal Ceroid Lipofuscinoses

Kline

Wishart²,

Mills³

et al. 2020

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

View full text Add to dashboard Cite

show abstract

NCLs and ER: A stressful relationship

Cited by 22 publications

References 107 publications

A first CLN6 variant case of late infantile neuronal ceroid lipofuscinosis caused by a homozygous mutation in a boy from China: a case report

A first CLN6 variant case of late infantile neuronal ceroid lipofuscinosis caused by a homozygous mutation in a boy from China: a case report

Lysosomal Storage Disorders Shed Light on Lysosomal Dysfunction in Parkinson’s Disease

Applying modern Omic technologies to the Neuronal Ceroid Lipofuscinoses

Contact Info

Product

Resources

About