A novel cathepsin D mutation in 2 siblings with late infantile neuronal ceroid lipofuscinosis

Thottath, Jineesh; Vellarikkal, Shamsudheen Karuthedath; Jayarajan, Rijith; Verma, Ankit; Manamel, Manu; Singh, Archana; Rajendran, Vidya; Sivasubbu, Sridhar; Scaria, Vinod

doi:10.1212/nxg.0000000000000302

Cited by 7 publications

(4 citation statements)

References 5 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Results from the present study will serve as a reference for ongoing work aimed at establishing treatments for retinal degeneration in CLN10 disease using AAV- and cell-based enzyme replacement strategies. Of interest in this context is that CLN10 patients carrying mutations in the CTSD gene that impair, but not completely abolish, the enzymatic activity of CTSD present with an infantile or juvenile disease onset and progressive retinal degeneration [ 20 , 21 , 35 ].…”

Section: Discussionmentioning

confidence: 99%

“…Progressive visual impairment as a result of retinal degeneration is among the characteristic clinical symptoms of most NCLs [ 13 , 34 ]. Ophthalmic examinations of CLN10 patients with an infantile or juvenile disease onset revealed the deterioration of the retinal function and retinal structure with similarities to retinitis pigmentosa, as assessed by electroretinogram recordings and fundus examinations, respectively [ 20 , 21 , 22 , 35 ]. A follow-up examination of one of these patients revealed retinal atrophy at advanced stages of the disease, demonstrating the progressive nature of retinal degeneration in CLN10 [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Rapid and Progressive Loss of Multiple Retinal Cell Types in Cathepsin D-Deficient Mice—An Animal Model of CLN10 Disease

Bassal

Liu

Jankowiak

et al. 2021

Cells

View full text Add to dashboard Cite

Vision loss is among the characteristic symptoms of neuronal ceroid lipofuscinosis (NCL), a fatal neurodegenerative lysosomal storage disorder. Here, we performed an in-depth analysis of retinal degeneration at the molecular and cellular levels in mice lacking the lysosomal aspartyl protease cathepsin D, an animal model of congenital CLN10 disease. We observed an early-onset accumulation of storage material as indicated by elevated levels of saposin D and subunit C of the mitochondrial ATP synthase. The accumulation of storage material was accompanied by reactive astrogliosis and microgliosis, elevated expression of the autophagy marker sequestosome 1/p62 and a dysregulated expression of several lysosomal proteins. The number of cone photoreceptor cells was reduced as early as at postnatal day 5. At the end stage of the disease, the outer nuclear layer was almost atrophied, and all cones were lost. A significant loss of rod and cone bipolar cells, amacrine cells and ganglion cells was found at advanced stages of the disease. Results demonstrate that cathepsin D deficiency results in an early-onset and rapidly progressing retinal dystrophy that involves all retinal cell types. Data of the present study will serve as a reference for studies aimed at developing treatments for retinal degeneration in CLN10 disease.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Rapid and Progressive Loss of Multiple Retinal Cell Types in Cathepsin D-Deficient Mice—An Animal Model of CLN10 Disease

Bassal

Liu

Jankowiak

et al. 2021

Cells

View full text Add to dashboard Cite

show abstract

“…Glycogen phosphorylase, brain form, is a lysosomal enzyme identified in our EL fraction that regulates glycogen mobilization ( Mathieu et al., 2016 ) and plays a prominent role as the only marker protein elevated in the early-stage of asymptomatic patients with Fabry disease ( Doykov et al., 2020 ). In addition, we identified a major complement of lysosomal cathepsins in our proteomic data that have been previously linked with cardiovascular diseases, including cathepsins B, C, D, and Z ( Guo et al., 2002 ; Moheimani et al., 2012 ; Wolinsky et al., 1978 ; Letronne et al., 2016 ; Wu et al, 2017 ; Thottath et al., 2019 ; Campden and Zhang, 2019 ). The successful identification of such disease-related proteins highlights the potential for use of these techniques in understanding the role of lysosomal proteins in pathology.…”

Section: Discussionmentioning

confidence: 99%

A modified density gradient proteomic-based method to analyze endolysosomal proteins in cardiac tissue

et al. 2021

View full text Add to dashboard Cite

Summary The importance of lysosomes in cardiac physiology and pathology is well established, and evidence for roles in calcium signaling is emerging. We describe a label-free proteomics method suitable for small cardiac tissue biopsies based on density-separated fractionation, which allows study of endolysosomal (EL) proteins. Density gradient fractions corresponding to tissue lysate; sarcoplasmic reticulum (SR), mitochondria (Mito) (1.3 g/mL); and EL with negligible contamination from SR or Mito (1.04 g/mL) were analyzed using Western blot, enzyme activity assay, and liquid chromatography with tandem mass spectrometry (LC-MS/MS) analysis (adapted discontinuous Percoll and sucrose differential density gradient). Kyoto Encyclopedia of Genes and Genomes, Reactome, Panther, and Gene Ontology pathway analysis showed good coverage of RAB proteins and lysosomal cathepsins (including cardiac-specific cathepsin D) in the purified EL fraction. Significant EL proteins recovered included catalytic activity proteins. We thus present a comprehensive protocol and data set of guinea pig atrial EL organelle proteomics using techniques also applicable for non-cardiac tissue.

show abstract

“…Biallelic mutations of the CTSD gene leading to NCL or NCL‐like disease have been reported in nine studies (Doccini et al, 2016 ; Fritchie et al, 2009 ; Hersheson et al, 2014 ; Meyer et al, 2015 ; Regensburger et al, 2020 ; Siintola et al, 2006 ; Steinfeld et al, 2006 ; Thottath et al, 2019 ; Varvagiannis et al, 2018 ), in which, 12 different mutations were identified from 10 families in total. Among those mutations, 4 of them were insertion or deletion mutations causing amino acid frameshift, and the other 8 were missense mutations.…”

Section: Discussionmentioning

confidence: 99%

The c.863A>G (p.Glu288Gly) variant of the CTSD gene is not associated with CLN10 disease

Yang

Ding

Meng

et al. 2021

Molec Gen & Gen Med

View full text Add to dashboard Cite

Neuronal ceroid lipofuscinoses (NCLs), also known as Batten disease, are a group of severe and progressive neurodegenerative disorders that are inherited in a predominantly recessive manner and have mostly characterized by childhood onset (Williams & Mole, 2012). NCL disease is characterized by a gradual decline in vision and cognitive and motor function, together with seizures and dementia in the most common types of NCLs (Haltia & Goebel, 2013;Nita et al., 2016;Williams & Mole, 2012). There are 14 genetically distinct NCL disorders, denoted as CLN1

show abstract

A novel cathepsin D mutation in 2 siblings with late infantile neuronal ceroid lipofuscinosis

Cited by 7 publications

References 5 publications

Rapid and Progressive Loss of Multiple Retinal Cell Types in Cathepsin D-Deficient Mice—An Animal Model of CLN10 Disease

Rapid and Progressive Loss of Multiple Retinal Cell Types in Cathepsin D-Deficient Mice—An Animal Model of CLN10 Disease

A modified density gradient proteomic-based method to analyze endolysosomal proteins in cardiac tissue

The c.863A>G (p.Glu288Gly) variant of the CTSD gene is not associated with CLN10 disease

Contact Info

Product

Resources

About