Reevaluation of Neuronal Ceroid Lipofuscinoses: Atypical Juvenile Onset May Be the Result of CLN2 Mutations

Wisniewski, K. E.; Kaczmarski, A.; Kida, E; Connell, Fred; Kaczmarski, Wojciech; Michalewski, Martin P.; Moroziewicz, Dorota; Zhong, Nan

doi:10.1006/mgme.1999.2814

Cited by 38 publications

(32 citation statements)

References 16 publications

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“…Under standard conditions, CHO cells expressing this mutant protein demonstrated $1.8% of the wtTPPI activity, similar to what we have observed previously in the frozen brain tissue of a compound heterozygote toward p.Arg447His and g.3556G4C ($2.2% of the control values) [Wisniewski et al, 2001]. Given that individuals carrying this mutation demonstrate a milder, protracted course of the disease in comparison with the classic phenotype [Wisniewski et al, 1999], our data suggest that even a very low level of TPPI activity is able to slow down the disease process. In agreement with these data obtained for human TPPI, mice homozygous toward the Arg446 mutation (an equivalent of human Arg447) also reveal a distinctly milder phenotype than animals with disruption of TPPI [Sleat et al, 2008].…”

Section: Discussionsupporting

confidence: 84%

“…CLN2 disease typically starts between 2 and 4 years of age with seizures, and decline in mental and motor abilities followed by cerebellar ataxia, visual loss, and pyramidal and extrapyramidal signs, leading to death in the first or second decade of life [Williams et al, 1999]. Clinical variability in CLN2 disease is low, and only a few cases with protracted/delayed course of the disease have been described [Elleder et al, 2008;Steinfeld et al, 2002;Wisniewski et al, 1999]. Lysosomal autofluorescent storage material rich in subunit c of mitochondrial ATPase accumulates in many types of cells in affected individuals.…”

Section: Introductionmentioning

confidence: 99%

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Functional consequences and rescue potential of pathogenic missense mutations in tripeptidyl peptidase I

2010

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There are 35 missense mutations among 68 different mutations in the TPP1 gene, which encodes tripeptidyl peptidase I (TPPI), a lysosomal aminopeptidase associated with classic late-infantile neuronal ceroid lipofuscinosis (CLN2 disease). To elucidate the molecular mechanisms underlying TPPI deficiency in patients carrying missense mutations and to test the amenability of mutant proteins to chemical chaperones and permissive temperature treatment, we introduced individually 14 disease-associated missense mutations into human TPP1 cDNA and analyzed the cell biology of these TPPI variants expressed in Chinese hamster ovary cells. Most TPPI variants displayed obstructed transport to the lysosomes, prolonged half-life of the proenzyme, and residual or no enzymatic activity, indicating folding abnormalities. Protein misfolding was produced by mutations located in both the prosegment (p.Gly77Arg) and throughout the length of the mature enzyme. However, the routes of removal of misfolded proteins by the cells varied, ranging from their efficient degradation by the ubiquitin/proteasome system to abundant secretion. Two TPPI variants demonstrated enhanced processing in response to folding improvement treatment, and the activity of one of them, p.Arg447His, showed a fivefold increase under permissive temperature conditions, which suggests that folding improvement strategies may ameliorate the function of some misfolding TPPI mutant proteins.

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Section: Discussionsupporting

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Functional consequences and rescue potential of pathogenic missense mutations in tripeptidyl peptidase I

2010

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“…The symptoms in classic or typical JNCL often begin after 4 years of age with progressive visual loss and other neurological dysfunction (dementia; seizures; pyramidal, extrapyramidal, and cerebellar signs). Before the recent progress in molecular genetic studies, diagnosis of NCLs was based on age at onset, clinical course, and pathological findings of fingerprint profiles and/or vacuoles in the lymphocytes by electron microscopy 10 . In 27 homozygous patients for the 1.02-kb deletion in Finland, visual failure was noticed at 4-10 years old (100%), onset of epilepsy at 8-13 years old (92%), parkinsonian signs at 12-15 years of age (30%) and at 17-29 years of age (22%); and death occurred between 10 and 28 year 11 .…”

Section: Introductionmentioning

confidence: 99%

Juvenile neuronal ceroid-lipofuscinosis: clinical and molecular investigation in a large family in Brazil

Valadares

Pizarro

Oliveira

et al. 2011

Arq. Neuro-Psiquiatr.

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Objective: Juvenile Neuronal Ceroid-Lipofuscinosis (JNCL, CLN 3, Batten Disease) (OMIM #204200) belongs to the most common group of neurodegenerative disorders of childhood. We report the clinical data and molecular analysis of a large Brazilian family. Method: Family composed of two consanguineous couples and thirty-two children. Clinical data of ten JNCL patients and molecular analyses on 13 participants were obtained. Results: The large 1.02 kb deletion was detected. The most severe phenotype, with autistic behavior, tics and parkinsonism was seen in a 12-year-old female and a milder phenotype in a 14-yearold male. Nyctalopia was the first symptom in one deceased child. The visual loss of six patients has been first observed in the school and not at home. Conclusion: The report highlights the phenotypical intrafamily variation in 10 affected children of this family. The molecular investigation of this large family in our metabolic center turned possible the diagnosis, right approach and genetic counseling. Key words: Batten disease, neuronal ceroid-lipofuscinoses, polymerase chain reaction.Lipofuscinose ceróide neuronal juvenil: investigação clínica e molecular em uma família grande no Brasil RESUMO Objetivo: Lipofuscinose Ceróide Neuronal Juvenil (JNCL, CLN 3, Doença de Batten) (OMIM # 204200) pertence ao grupo mais comum de doenças neurodegenerativas na infância. É causada por mutações no gene CLN3, com padrão de herança recessiva. A deleção de 1,02 kb é a mutação mais comum. Relatamos os dados clínicos e análise molecular de uma família consanguínea numerosa. Método: Família composta por dois casais consanguíneos e trinta e duas crianças. Foram obtidos dados clínicos de dez pacientes e análises moleculares de 13 participantes. Resultados: Foi detectada deleção de 1,02 kb. O fenótipo mais grave, com comportamento autista, tiques e parkinsonismo foi visto em uma paciente do sexo feminino de 12 anos e o fenótipo mais leve em um paciente do sexo masculino de 14 anos. Nictalopia foi o primeiro sintoma de uma criança falecida. A perda visual de seis pacientes foi observada pela primeira vez na escola e não em casa. Conclusão: Destaca-se a variação fenotípica intrafamiliar em 10 pacientes. A investigação molecular desta família numerosa tornou possível o diagnóstico, a abordagem correta e aconselhamento genético. Palavras-chave: doença de Batten, lipofuscinoses ceróides neuronais, reação em cadeia da polimerase.

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“…Patients with naturally occurring mutations in TPP I develop, by the age of 2-4 years, seizures and cognitive decline, followed by visual loss and cerebellar, pyramidal, and extrapyramidal signs, causing death in the second decade of life (8). Rare mutations leading to preservation of residual TPP I activity cause protracted, slightly milder clinical phenotypes (9,10).…”

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confidence: 99%

Maturation of Human Tripeptidyl-peptidase I in Vitro

Golabek

Wujek

Walus

et al. 2004

Journal of Biological Chemistry

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Tripeptidyl-peptidase I (TPP I, CLN2 protein) is a lysosomal aminopeptidase that cleaves off tripeptides from the free N termini of oligopeptides and also shows minor endopeptidase activity. TPP I is synthesized as a preproenzyme. Its proenzyme autoactivates under acidic conditions in vitro, resulting in a rapid conversion into the mature form. In this study, we examined the process of maturation in vitro of recombinant latent human TPP I purified to homogeneity from secretions of Chinese hamster ovary cells overexpressing TPP I cDNA. Autoprocessing of TPP I proenzyme was carried out at a wide pH range, from ϳ2.0 to 6.0, albeit with different efficiencies depending on the pH and the type of buffer. However, the acquisition of enzymatic activity in the same buffer took place in a narrower pH "window," usually in the range of 3.6 -4.2. N-terminal sequencing revealed that mature, inactive enzyme generated during autoactivation at higher pH contained N-terminal extensions (starting at 6 and 14 amino acid residues upstream of the prosegment/mature enzyme junction), which could contribute to the lack of activity of TPP I generated in this manner. Autoprocessing was not associated with any major changes of the secondary structure of the proenzyme, as revealed by CD spectroscopy. Both the activation and proteolytic processing of the recombinant TPP I precursor were primarily concentration-independent. The addition of the mature enzyme did not accelerate the processing of the proenzyme. In addition, the maturation of the proenzyme was not affected by the presence of glycerol. Finally, the proenzyme with the active site mutated (S475L) was not processed in the presence of the wild-type enzyme. All of these findings indicate a primarily intramolecular (unimolecular) mechanism of TPP I activation and autoprocessing and suggest that in vivo mature enzyme does not significantly participate in its own generation from the precursor.

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Reevaluation of Neuronal Ceroid Lipofuscinoses: Atypical Juvenile Onset May Be the Result of CLN2 Mutations

Cited by 38 publications

References 16 publications

Functional consequences and rescue potential of pathogenic missense mutations in tripeptidyl peptidase I

Functional consequences and rescue potential of pathogenic missense mutations in tripeptidyl peptidase I

Juvenile neuronal ceroid-lipofuscinosis: clinical and molecular investigation in a large family in Brazil

Maturation of Human Tripeptidyl-peptidase I in Vitro

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