Mutation update: Review of
            <i>TPP1</i>
            gene variants associated with neuronal ceroid lipofuscinosis CLN2 disease

Gardner, Emily; Bailey, Mitch; Schulz, Angela; Aristorena, Mikel; Miller, Nicole L.; Mole, Sara

doi:10.1002/humu.23860

Cited by 54 publications

(68 citation statements)

References 64 publications

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“…and therefore, unless there is a familial history, irreversible neurodegeneration has usually occurred before a diagnosis is made (31) The aim of this programme was to use a robust systematic approach to develop consensus- These guidelines covers the whole spectrum of the disorder. They all focus on the following main areas: that diagnosis must be confirmed and secure before the onset of therapy, baseline assessment should be performed before the onset of treatment and may include but is not limited to language ability, motor ability, feeding status, seizures, myoclonus and vision.…”

Section: Discussionmentioning

confidence: 99%

Guidelines on the Diagnosis, Clinical Assessments, Treatment and Management for CLN2 Disease Patients

Mole

Schulz

Badoe

et al. 2020

Preprint

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Background: CLN2 disease (Neuronal Ceroid Lipofuscinosis Type 2), or Late-Infantile Neuronal Ceroid Lipofuscinosis (LINCL), is an ultra-rare, neurodegenerative lysosomal storage disease, caused by an enzyme deficiency of tripeptidyl peptidase 1 (TPP1). Lack of disease awareness and the non-specificity of presenting symptoms often leads to delayed diagnosis. These guidelines provide robust evidence-based, expert-agreed recommendations on the risks/benefits of disease-modifying treatments and the medical interventions used to manage this condition. Methods: An expert mapping tool process was developed ranking multidisciplinary professionals, with knowledge of CLN2 disease, diagnostic or management experience of CLN2 disease, or family support professionals. Individuals were sequentially approached to identify two chairs, ensuring that the process was transparent and unbiased. A systematic literature review of published evidence using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidance was independently and simultaneously conducted to develop key statements based upon the strength of the publications. Clinical care statements formed the basis of an international modified Delphi consensus determination process using the virtual meeting (Within3) online platform which requested experts to agree or disagree with any changes. Statements reaching the consensus mark became the guiding statements within this manuscript, which were subsequently assessed against the Appraisal of Guidelines for Research and Evaluation (AGREEII) criteria.Results: Twenty-one international experts from 7 different specialities, including a patient advocate, were identified. Fifty-three guideline statements were developed covering 13 domains: General Description and Statements, Diagnostics, Clinical Recommendations and Management, Assessments, Interventions and Treatment, Additional Care Considerations, Social Care Considerations, Pain Management, Epilepsy / Seizures, Nutritional Care Interventions, Respiratory Health, Sleep and Rest, and End of Life Care. Consensus was reached after a single round of voting, with one exception which was revised, and agreed by 100% of the SC and achieved 80% consensus in the second voting round. The overall AGREE II assessment score obtained for the development of the guidelines was 5.7 (where 1 represents the lowest quality, and 7 represents the highest quality). Conclusion: This program provides robust evidence- and consensus-driven guidelines that can be used by all healthcare professionals involved in the management of patients with CLN2 disease. This addresses the clinical need to complement other information available.

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Section: Discussionmentioning

confidence: 99%

Guidelines on the Diagnosis, Clinical Assessments, Treatment and Management for CLN2 Disease Patients

Mole

Schulz

Badoe

et al. 2020

Preprint

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“…Mutations or inhibition of the TPP1/POT1 subunit increases the telomere length, which clearly shows that TPP1/POT1 subunit is essentially required to inhibit the elongation of telomere [64,67]. A nonsense mutation p.Q320X in the TPP1 gene was recently identified which disrupts the POT1 and TIN2 binding, which ultimately resulted in the formation of a non-functional shelterin complex [113]. In consistence, mutations such as p.V272M and p.N249S were identified in the lower-density melanomas, whereas p.A200T and p.I322F mutations were observed in the CMM patients.…”

Section: Tpp1mentioning

confidence: 99%

Structural Features of Nucleoprotein CST/Shelterin Complex Involved in the Telomere Maintenance and Its Association with Disease Mutations

Amir

Khan

Queen

et al. 2020

Cells

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Telomere comprises the ends of eukaryotic linear chromosomes and is composed of G-rich (TTAGGG) tandem repeats which play an important role in maintaining genome stability, premature aging and onsets of many diseases. Majority of the telomere are replicated by conventional DNA replication, and only the last bit of the lagging strand is synthesized by telomerase (a reverse transcriptase). In addition to replication, telomere maintenance is principally carried out by two key complexes known as shelterin (TRF1, TRF2, TIN2, RAP1, POT1, and TPP1) and CST (CDC13/CTC1, STN1, and TEN1). Shelterin protects the telomere from DNA damage response (DDR) and regulates telomere length by telomerase; while, CST govern the extension of telomere by telomerase and C strand fill-in synthesis. We have investigated both structural and biochemical features of shelterin and CST complexes to get a clear understanding of their importance in the telomere maintenance. Further, we have analyzed ~115 clinically important mutations in both of the complexes. Association of such mutations with specific cellular fault unveils the importance of shelterin and CST complexes in the maintenance of genome stability. A possibility of targeting shelterin and CST by small molecule inhibitors is further investigated towards the therapeutic management of associated diseases. Overall, this review provides a possible direction to understand the mechanisms of telomere borne diseases, and their therapeutic intervention.

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“…In CLN2 disease, approximately, 60% of patients have one of two pathogenic variants (c.509-1G>C and c.622C>T [p.(Arg208*)]). These mutations may be found in a homozygous state but are also commonly present in a compound heterozygous state (Gardner et al, 2019;Lojewski et al, 2014). Lojewski et al (2014) AAF-AMC: Ala-Ala-Phe-7-amido-4-methylcoumarin; AFU: Arbitrary fluorescence units; AMC: 7-amino-4methylcoumarin; CLN: Ceroid lipofuscinosis, neuronal; CRISPR: Clustered regularly interspaced short palindromic repeats; Cas9: CRISPR-associated protein 9; gRNA: Guide RNA; hESC: Human embryonic stem cell; iPSC: Induced pluripotent stem cell; NCL: Neuronal ceroid lipofuscinosis; PAM: Protospacer adjacent motif; ROCKi: Rho-associated protein kinase inhibitor; ssODN: Single-stranded oligodeoxyribonucleotide; TPP1: Tripeptidyl peptidase 1.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Generation of PathogenicTPP1Mutations in Human Stem Cells as a Model for CLN2 Disease

Prada

Schmidt³

et al. 2021

Preprint

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Neuronal ceroid lipofuscinosis type 2 (CLN2 disease) is an autosomal recessive neurodegenerative disorder generally with onset at 2 to 4 years of age and characterized by seizures, loss of vision, progressive motor and mental decline, and premature death. CLN2 disease is caused by loss-of-function mutations in the tripeptidyl peptidase 1 (TPP1) gene leading to deficiency in TPP1 enzyme activity. Approximately 60% of patients have one of two pathogenic variants (c.509-1G>C or c.622C>T [p.(Arg208*)]). In order to generate a human stem cell model of CLN2 disease, we used CRISPR/Cas9-mediated knock-in technology to introduce these mutations in a homozygous state into H9 human embryonic stem cells. Heterozygous lines of the c.622C>T (p.(Arg208*)) mutation were also generated, which included a heterozygous mutant with a wild-type allele and different compound heterozygous coding mutants resulting from indels on one allele. We describe the methodology that led to the generation of the lines and provide data on the initial validation and characterization of these CLN2 disease models. Notably, both mutant lines (c.509-1G>C and c.622C>T [p.(Arg208*)]) in the homozygous state were shown to have reduced or absent protein, respectively, and deficiency of TPP1 enzyme activity. These models, which we are making available for wide-spread sharing, will be useful for future studies of molecular and cellular mechanisms underlying CLN2 disease and for therapeutic development.

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Mutation update: Review of TPP1 gene variants associated with neuronal ceroid lipofuscinosis CLN2 disease

Cited by 54 publications

References 64 publications

Guidelines on the Diagnosis, Clinical Assessments, Treatment and Management for CLN2 Disease Patients

Guidelines on the Diagnosis, Clinical Assessments, Treatment and Management for CLN2 Disease Patients

Structural Features of Nucleoprotein CST/Shelterin Complex Involved in the Telomere Maintenance and Its Association with Disease Mutations

Generation of PathogenicTPP1Mutations in Human Stem Cells as a Model for CLN2 Disease

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