Two novel CLN5 mutations in a Portuguese patient with vLINCL: Insights into molecular mechanisms of CLN5 deficiency

Bessa, Carlos; Teixeira, Carla; Mangas, M.; Dias, Ana Cristi Basile; Sá-Miranda, Clara; Guimarães, André Vicente; Ferreira, João Boavida; Canas, Nuno; Cabral, Pedro; Ribeiro, Maria Gil

doi:10.1016/j.ymgme.2006.04.010

Cited by 32 publications

(44 citation statements)

References 34 publications

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“…In humans, the CLN5 gene maps to chromosome 13q22, consists of 4 exons spanning 13 kb of genomic DNA, and encodes a protein of 407 amino acids. The predicted amino acid sequence of CLN5 shows no homology to previously reported proteins, and although several studies suggested that CLN5 has at least one transmembrane domain (4,33,38), other studies report that it may be a soluble protein (16). Whereas transfection of COS-1 cells with CLN5 cDNA results in the synthesis of a highly glycosylated 60-kDa polypeptide, 47-, 44-, 42-, and 40-kDa polypeptides were produced in cell-free translation assays due to usage of the alternative initiator methionine (17).…”

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confidence: 63%

The Role of Ceroid Lipofuscinosis Neuronal Protein 5 (CLN5) in Endosomal Sorting

Mamo

Jules

Dumaresq-Doiron

et al. 2012

Molecular and Cellular Biology

106

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cMutations in the gene encoding CLN5 are the cause of Finnish variant late infantile Neuronal Ceroid Lipofuscinosis (NCL), and the gene encoding CLN5 is 1 of 10 genes (encoding CLN1 to CLN9 and cathepsin D) whose germ line mutations result in a group of recessive disorders of childhood. Although CLN5 localizes to the lysosomal compartment, its function remains unknown. We have uncovered an interaction between CLN5 and sortilin, the lysosomal sorting receptor. However, CLN5, unlike prosaposin, does not require sortilin to localize to the lysosomal compartment. We demonstrate that in CLN5-depleted HeLa cells, the lysosomal sorting receptors sortilin and cation-independent mannose 6-phosphate receptor (CI-MPR) are degraded in lysosomes due to a defect in recruitment of the retromer (an endosome-to-Golgi compartment trafficking component). In addition, we show that the retromer recruitment machinery is also affected by CLN5 depletion, as we found less loaded Rab7, which is required to recruit retromer. Taken together, our results support a role for CLN5 in controlling the itinerary of the lysosomal sorting receptors by regulating retromer recruitment at the endosome.

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mentioning

confidence: 63%

The Role of Ceroid Lipofuscinosis Neuronal Protein 5 (CLN5) in Endosomal Sorting

Mamo

Jules

Dumaresq-Doiron

et al. 2012

Molecular and Cellular Biology

106

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“…Another consanguineous Asian family, of Afghan origin, was also identified with a mutation in CLN5. During the course of this study other reports have been published describing European, non-Finnish CLN5 patients (Bessa et al, 2006;Cannelli et al, 2007). The patients reported here represent the first cases of NCL disease caused by mutations in CLN5 originating from the Indian subcontinent.…”

Section: Introductionmentioning

confidence: 77%

Retention of lysosomal protein CLN5 in the endoplasmic reticulum causes neuronal ceroid lipofuscinosis in Asian Sibship

et al. 2009

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ABSTRACT:The neuronal ceroid lipofuscinoses (NCLs) form a group of autosomal recessively inherited neurodegenerative disorders that mainly affect children. Ten NCL forms can be distinguished by age at onset, clinicopathologic features, and genetics. In eight of these forms, the underlying genes have been identified. At present, approximately 10% of all patients do not fall into one of the eight known genetic forms of NCL. We have identified two Asian families with two novel homozygous mutations in the CLN5 gene. In the first Pakistani family, two children developed symptoms of an early juvenile NCL. After exclusion of mutations in genes known to be associated with this age of onset in families from many different countries (CLN1, CLN2, CLN3, CLN6, CLN8 and CLN10) SNP array-based homozygosity mapping led to the identification of a novel homozygous mutation c.1072_1073delTT (p.Leu358AlafsX4) in CLN5. In the second Afghan family, two children developed symptoms of a late infantile NCL. The mutation c.1137G>T (p.Trp379Cys) in CLN5 was identified. The affected children in these families represent the first reported CLN5 patients originating in Asian sibships. Expression analysis showed that mutant p.Leu358AlafsX4 CLN5 is truncated and lacks a used N-glycosylation site at Asn401. The missense mutation p.Trp379Cys affected neither the size nor glycosylation of the CLN5 protein. Double immunofluorescence microscopy showed that while the wild-type CLN5 protein is localized in lysosomes, both mutant CLN5 proteins are retained in the endoplasmic reticulum rather than reaching the lysosome.

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“…Additionally, we analyzed the recently described, but also uncharacterized disease mutations at amino acid 112, found in a Portuguese family (p.R112P; POR) and a Colombian patient (p.R112H; COL). The Portuguese patient is a compound heterozygous carrying a null mutation (p.Q189X) in one allele and two mutations (p.R112P and p.D279N) in the other allele [Bessa et al, 2006]. The Colombian patient has been described to present a juvenile-onset phenotype [Pineda-Trujillo et al, 2005].…”

Section: S] Methionine (B)mentioning

confidence: 99%

“…Due to eight potential N-glycosylation sites, the CLN5 protein has been shown to have an observed molecular mass of 52-75 kDa with both high mannose-type and complex-type sugars Vesa et al, 2002]. The solubility of the CLN5 protein has been controversially discussed [Bessa et al, 2006;Isosomppi et al, 2002;Savukoski et al, 1998;Vesa et al, 2002]. However, it has been reported that human CLN5 contains mannose 6-phosphate (Man 6-P) residues on high mannose-type oligosaccharides linked to Asn320, Asn330, and Asn401, supporting the existence of soluble CLN5 variants [Sleat et al, 2006].…”

Section: Introductionmentioning

confidence: 99%

The neuronal ceroid lipofuscinosis protein CLN5: new insights into cellular maturation, transport, and consequences of mutations

et al. 2010

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Neuronal ceroid lipofuscinoses (NCLs) represent a group of children's inherited neurodegenerative disorders caused by mutations in at least eight different genes. Mutations in the CLN5 gene result in the Finnish variant late infantile NCL characterized by gradual loss of vision, epileptic seizures, and mental deterioration. The CLN5 gene encodes a lysosomal glycoprotein of unidentified function. In this study, we have used both transient and stable expression systems for the characterization of CLN5, focusing on the localization, processing, and intracellular trafficking. We show that CLN5 is proteolytically cleaved, and that the mature polypeptide is transported to the lysosomes. Our data provide the first evidence that soluble CLN5 protein can also undergo mannose-6-phosphate receptor-independent trafficking to the lysosomes. We studied the localization and maturation of the CLN5 carrying the previously uncharacterized vLINCL disease causing mutations in HeLa cells. All analyzed disease mutations disturb the lysosomal trafficking of the mutated CLN5 proteins. The level of lysosomal targeting does not correlate, however, to disease onset, indicating that CLN5 may also function outside lysosomes. This study furthers our understanding of the basic properties of the CLN5 protein, necessary for the characterization of the consequences of disease mutations and for the planning of future therapies for vLINCL.

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Two novel CLN5 mutations in a Portuguese patient with vLINCL: Insights into molecular mechanisms of CLN5 deficiency

Cited by 32 publications

References 34 publications

The Role of Ceroid Lipofuscinosis Neuronal Protein 5 (CLN5) in Endosomal Sorting

The Role of Ceroid Lipofuscinosis Neuronal Protein 5 (CLN5) in Endosomal Sorting

Retention of lysosomal protein CLN5 in the endoplasmic reticulum causes neuronal ceroid lipofuscinosis in Asian Sibship

The neuronal ceroid lipofuscinosis protein CLN5: new insights into cellular maturation, transport, and consequences of mutations

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