Alternative titles; symbols
HGNC Approved Gene Symbol: TPP1
SNOMEDCT: 785301002;
Cytogenetic location: 11p15.4 Genomic coordinates (GRCh38) : 11:6,612,768-6,619,422 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11p15.4 | Ceroid lipofuscinosis, neuronal, 2 | 204500 | Autosomal recessive | 3 |
| Spinocerebellar ataxia, autosomal recessive 7 | 609270 | Autosomal recessive | 3 |
TPP1 (EC 3.4.14.9) is a lysosomal exopeptidase that sequentially removes tripeptides from the N termini of proteins. It also has a minor endoprotease activity (Golabek et al., 2005).
Sleat et al. (1997) used an approach applicable to other lysosomal storage diseases to identify the molecular basis of 'late infantile neuronal ceroid lipofuscinosis' (LINCL, or CLN2; 204500). By purifying mannose 6-phosphate-containing glycoproteins, which are present on newly synthesized lysosomal enzymes, from normal brain by affinity chromatography and fractionation by SDS-polyacrylamide gel electrophoresis, they identified a single protein absent in CLN2 specimens. Comparisons with EST databases resulted in the assembly of a nearly complete sequence for the human CLN2 gene. Northern blot analysis showed 2 transcripts, and mRNA was detected in all tissues examined with highest levels in heart and placenta. The CLN2 transcript encodes a 563-residue protein with a molecular mass of 46 kD. Sequence comparisons suggested that this protein is a pepstatin-insensitive lysosomal peptidase.
Liu et al. (1998) reported the complete sequence of the CLN2 gene.
Golabek et al. (2003) stated that TPP1 encodes a 563-amino acid preproenzyme with a 19-amino acid signal peptide and a 176-amino acid prodomain that are removed during maturation, yielding a 368-amino acid mature enzyme. TPP1 also contains 5 N-glycosylation sites. The proenzyme has an apparent molecular mass of 66 kD, and the mature enzyme has an apparent molecular mass of 46 to 48 kD.
Liu et al. (1998) determined that the CLN2 gene contains 13 exons and spans 6.65 kb.
By genomewide analysis, Haines et al. (1998) mapped the CLN2 gene to chromosome 11p15.5.
Using immunostaining and confocal microscopy, Golabek et al. (2003) found that TPP1 was present in lysosomes of Chinese hamster ovary cells expressing human TPP1, similar to the endogenous enzyme in human cells. Immunoblot analysis of cell lysates revealed a 68-kD precursor that was converted to a mature 48-kD enzyme. Compounds affecting the pH of intracellular acidic compartments and those interfering with intracellular vesicular transport, as well as inhibition of fusion between late endosomes and lysosomes, hampered conversion of TPP1 proenzyme into the mature form, suggesting that this process takes place in lysosomes. Digestion of immunoprecipitated TPP1 with glycosidases or chemical inhibition of N-glycosylation in cells reduced the molecular mass of TPP1 proenzyme by about 10 kD, indicating that all 5 N-glycosylation sites of TPP1 are used. Further analysis showed that a serine protease sensitive to the inhibitor AEBSF participated in processing the TPP1 proenzyme to the mature form in vivo.
TPP1 proenzyme autoactivates in vitro via an unimolecular mechanism. Golabek et al. (2005) found that high ionic strength and glycosaminoglycans (GAGs) increased yield (ionic strength) or yield and rate (GAGs) of TPP1 activation, enhanced degradation of liberated TPP1 prosegment fragments, and increased the pH of autoactivation up to 6.0. Although ionic strength and GAGs also inhibited TPP1 activity in vitro and in living cells, the degree of inhibition (from 20 to 60%) appeared to be of limited functional significance. Binding of TPP1 to GAGs improved its thermal stability and protected the enzyme against alkaline pH-induced denaturation in vitro and in vivo. Golabek et al. (2005) concluded that TPP1 can be autoactivated in vivo at lysosomal pH and that GAGs can regulate this process.
Oyama et al. (2005) purified recombinant human TPP1 from virus-TPP1-infected silkworm pupae and found that it had been processed to the mature enzyme. Using a synthetic substrate, they showed that mature TPP1 was stable in a pH range of 2.5 to 5.0, with an optimum pH for activity of 4.0; activity was lost above pH 7. Oyama et al. (2005) identified ser280, glu77, and asp81 (numbering of the mature enzyme) as catalytic residues by mutational analysis, inhibition studies, and sequence similarity with other family members.
Neuronal Ceroid Lipofuscinosis 2
In patients with late-infantile onset of CLN2 (204500), Sleat et al. (1997) identified mutations in the CLN2 gene (607998.0001-607998.0004).
In 2 unrelated patients, originally diagnosed with juvenile-onset CLN3 (204200) on the basis of age at onset, age at death, and inclusion morphology, Sleat et al. (1999) identified a rare monoallelic mutation that resulted in an arg447-to-his (R447H) substitution in the CLN2 gene (607998.0005).
Defects in the CLN2 gene do not appear to be responsible for adult NCL (CLN4; 204300), or Kufs disease, as CLN2 protease activities are the same as or higher than controls in adult NCL lymphoblasts (Sohar et al., 1999).
Mole et al. (1999) tabulated the reported mutations and polymorphisms in the CLN genes. The largest number of mutations, 26, had been identified in the CLN2 gene.
Moore et al. (2008) identified 5 different mutations in the CLN2 gene (see, e.g., 607998.0007) in affected members of 18 CLN2 families from Newfoundland. Among a total of 28 CLN families in this population, CLN2 showed the highest incidence of 1 in 11,161 live births.
Walus et al. (2010) expressed 14 disease-associated missense TPP1 mutations (see, e.g., C365R, 607998.0001; R447H, 607998.0005; R206C, 607998.0006; G284V, 607998.0007; N286S, 607998.0008), into Chinese hamster ovary cells. Most variants showed folding abnormalities, resulting in obstructed transport to the lysosomes, prolonged half-life of the proenzyme, and significantly reduced or no enzymatic activity. Many of the mutant proteins were retained in the ER. The routes of removal of misfolded proteins by the cells varied, ranging from efficient degradation by the ubiquitin/proteasome system to abundant secretion. Two TPPI variants (V277M and R447H) demonstrated enhanced processing in response to folding improvement with molecular chaperones, and R447H showed a 5-fold increase in activity under permissive temperature conditions, suggesting that folding improvement strategies may ameliorate the function of some misfolding TPPI mutant proteins.
In 2 sibs, born to consanguineous parents, with CLN2, Steigerwald et al. (2023) identified a homozygous splice site mutation in the TPP1 gene (c.1146-199G-A, 607998.0012). The mutation was identified by long-read sequencing (LRS) of the TPP1 gene. TPP1 enzyme activity was absent in leukocytes from one of the sibs and in a CVS sample and blood spot from the other sib.
Spinocerebellar Ataxia 7, Autosomal Recessive
In affected members of a Dutch family with autosomal recessive spinocerebellar ataxia-7 (SCAR7; 609270), originally reported by Breedveld et al. (2004), Sun et al. (2013) identified compound heterozygous mutations in the TPP1 gene: a splice site mutation resulting in premature termination (607998.0004) and a missense mutation (V466G; 607998.0010). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. An unrelated Dutch woman with the disorder was also found to be compound heterozygous for these 2 mutations, although a founder effect could not be confirmed. Residual TPP1 activity in patient lymphocytes was 10 to 15% that of controls, with 5% activity in patient fibroblasts. Electron microscopic analysis of 1 patient's skin fibroblasts showed some granular osmiophilic deposits (GROD) and fingerprint profiles, but no curvilinear profiles. Analysis of the unrelated Dutch woman's fibroblasts showed no abnormalities. Sun et al. (2013) suggested that V466G yields a hypomorphic allele with residual functional TPP1 activity, which likely resulted in a later age at onset and less severe phenotype in patients with SCAR7 compared to patients with CLN2.
In an 11-year-old girl with SCAR7, Dy et al. (2015) identified compound heterozygous mutations in the TPP1 gene: the common splice site mutation (607998.0004) and a missense mutation (E343D; 607998.0011). The mutations were found by whole-exome sequencing. TPP1 activity in patient cells was significantly decreased (3 to 15%) compared to controls.
Bessa et al. (2008) reported a 40-year-old Portuguese man with a mild protracted form of CLN2 who was homozygous for a mutation that created a potential acceptor site in intron 7 of the TPP1 gene (IVS7AS-10A-G; 607998.0009), predicted to result in a protein with 3 extra amino acids between codons 295 and 296 and not affecting the wildtype splice site. The patient had onset at age 10 years of progressive cognitive and motor dysfunction and seizures. Western blot analysis detected a 60% reduction in overall TPP1 protein levels, suggesting that the mutant protein had decreased stability. Bessa et al. (2008) concluded that the mutant protein retained enzyme activity, which was consistent with the milder phenotype.
Sleat et al. (2004) found that mice with targeted homozygous disruption of the Tpp1 gene were viable and healthy at birth, but developed progressive neurologic deterioration around 7 weeks of age. Clinical features included tremor and ataxia, and neuropathologic examination showed extensive neuronal pathology with accumulation of autofluorescent cytoplasmic storage material within the lysosomal-endosomal compartment, loss of cerebellar Purkinje cells, and widespread axonal degeneration. The life span of mutant mice was significantly decreased compared to wildtype. The findings recapitulated the features of human CLN2.
Sleat et al. (2008) generated mouse models of CLN2 with different hypomorphic Tpp1 mutations. Mice who were homozygous for R446H, which is analogous to human R447H (607998.0005), had approximately 6% residual brain activity of Tpp1. Mice who were compound heterozygous for the R446H allele and a null allele had about 3% residual Tpp1 activity and showed delayed disease onset and longer survival compared to homozygous-null mice. Homozygosity for R446H resulted in dramatic attenuation of disease, with even further expanded life span. The findings indicated that residual levels of Tpp1 can ameliorate disease, which has potential therapeutic implications for humans with the disorder.
In 2 unrelated patients with late-infantile onset of neuronal ceroid lipofuscinosis-2 (CLN2; 204500), Sleat et al. (1997) identified different mutation at the cys365 codon in the CLN2 gene. In 1 patient, a monoallelic T-to-C transition resulted in a cys365-to-arg substitution (C365R); presumably, the defect in this patient was compound heterozygous and there was an additional, unidentified mutation. In the second patient the mutation was homozygous (607998.0002).
In a patient with late-infantile onset of neuronal ceroid lipofuscinosis-2 (CLN2; 204500), Sleat et al. (1997) identified homozygosity for a G-to-A transition in the TPP1 gene that resulted in a cys365-to-tyr (C365Y) amino acid substitution. The authors identified a different mutation at the same codon in heterozygosity in another patient (607998.0002). Since this cysteine proved to be involved in disulfide bonding, Sleat et al. (1997) predicted that these mutations are probably highly disruptive given the role of disulfide bonds in establishing and maintaining protein structure.
In 2 sibs with late-infantile onset of neuronal ceroid lipofuscinosis-2 (CLN2; 204500), Sleat et al. (1997) found compound heterozygosity for a C-to-T transition that resulted in the conversion of codon 208 (CGA) to a stop codon (TGA). In the other allele, the conserved AG of the intronic 3-prime splice junction sequence was changed to AC, which was predicted to result in intron splicing (607998.0004). Each parent possessed a single different mutant allele.
Sleat et al. (1997) described compound heterozygosity in 2 sibs with late-infantile onset of neuronal ceroid lipofuscinosis-2 (CLN2; 204500). One allele of the CLN2 gene carried the R208X nonsense mutation (607998.0003); the other allele showed a splice site mutation, a G-to-C transversion of the consensus AG 3-prime splice acceptor site immediately preceding 523T of the cDNA sequence.
In affected members of a Dutch family with autosomal recessive spinocerebellar ataxia-7 (SCAR7; 609270), originally reported by Breedveld et al. (2004), Sun et al. (2013) identified compound heterozygous mutations in the TPP1 gene: a G-to-C transversion in intron 5 (c.509-1G-C) resulting in a frameshift and premature termination (Val170GlyfsTer29), and V466G (607998.0010). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. An unrelated Dutch woman with the disorder was also found to be compound heterozygous for these 2 mutations, although a founder effect could not be confirmed. Residual TPP1 activity in patient lymphocytes was 10 to 15% that of controls, with 5% activity in patient fibroblasts.
In an 11-year-old girl with SCAR7, Dy et al. (2015) identified compound heterozygous mutations in the TPP1 gene: c.509-1G-C, and a missense mutation (E343D; 607998.0011).
In 2 unrelated patients with juvenile-onset neuronal ceroid lipofuscinosis-2 (CLN2; 204500), Sleat et al. (1999) identified a rare monoallelic mutation that resulted in an arg447-to-his (R447H) substitution in the CLN2 gene. Both of these patients were compound heterozygous, with either a monoallelic common splice junction mutation (607998.0004) or the arg208-to-ter mutation (R208X; 607998.0003). Both patients were originally diagnosed with juvenile-onset CLN3 (204200) on the basis of age at onset, age at death, and inclusion morphology. Sleat et al. (1999) considered it likely that the R447H mutation caused incomplete loss of function of the CLN2 protease, resulting in the protracted phenotype. The findings indicated that an attenuated form of CLN2 (i.e., with juvenile onset) may not be correctly diagnosed or may be confused with other later-onset neurodegenerative disorders. Such observations are not uncommon with other lysosomal storage diseases, in which missense mutations result in a partial dysfunction and subsequent mild or protracted phenotype. The possible phenotype of an individual homozygous for the R447H allele remained unknown.
In a family with first-cousin parents, Berry-Kravis et al. (2000) demonstrated a 3664C-T transition in the CLN2 gene, resulting in an arg206-to-cys mutation (R206C), as the cause of late-infantile onset of neuronal ceroid lipofuscinosis-2 (CLN2; 204500) and used the mutation successfully for prenatal diagnosis, demonstrating that the fetus at risk was homozygous for the wildtype alleles. The homozygous proband had developed seizures at age 3 years and was unable to ambulate independently by age 5. Electron microscopy performed on a skin biopsy demonstrated curvilinear bodies typical of CLN2.
In affected members of 11 of 20 Canadian families with late-infantile onset of neuronal ceroid lipofuscinosis-2 (CLN2; 204500), Ju et al. (2002) identified a gly284-to-val (G284V) mutation in the CLN2 gene, which represented 55% and 32.5% of families and alleles, respectively, in this study. The authors referred to this mutation as the Canadian mutation, noting that it had not been found in any other population.
Moore et al. (2008) identified a homozygous G284V mutation in affected members from 5 families from Newfoundland with CLN2.
In 2 unrelated female patients of Kurdish ethnicity with late infantile neuronal ceroid lipofuscinosis-2 (CLN2; 204500), Steinfeld et al. (2002) identified a homozygous A-to-G transition at nucleotide 857 in exon 7 of the TPP1 gene. The mutation resulted in an asn286-to-ser (N286S) substitution that altered 1 of 5 N-glycosylation sites in the TPP1 protein. Both patients had a more protracted clinical course compared with patients with typical disease progression.
By transient transfection analysis in human embryonic kidney cells, Tsiakas et al. (2004) found that TPP1 containing the N286S mutation was synthesized and sorted in the Golgi like wildtype TPP1, but it was expressed at a lower level and was enzymatically inactive. TPP1 with the N286 mutation had an apparent molecular mass 2 kD lower than that of wildtype TPP1, whereas deglycosylation of mutant and wildtype TPP1 led to proteins of the same size. Tsiakas et al. (2004) concluded that TPP1 with the N286S mutation lacks 1 oligosaccharide chain, resulting in enzymatic inactivation and possibly prelysosomal protein degradation.
In a 40-year-old Portuguese man with a mild protracted form of neuronal ceroid lipofuscinosis-2 (CLN2; 204500), Bessa et al. (2008) identified a homozygous A-to-G transition in intron 7 (IVS7AS-10A-G) of the TPP1 gene, which created a potential acceptor site predicted to result in 3 extra amino acids between codons 295 and 296 and not affecting the wildtype splice site. At age 10 years, the patient had onset of progressive cognitive and motor dysfunction and seizures. Leukocytes and fibroblasts showed decreased TPP1 activity compared to controls, but activity was about 2-fold higher than that associated with TPP1-null mutations. Northern blot analysis found normal levels of correctly spliced CLN2 mRNA in patient fibroblasts, but cDNA sequencing showed the retention of 9 nucleotides from intron 7, showing that the alternative splice site was used. Western blot analysis detected a 60% reduction in overall TPP1 protein levels, suggesting that the mutant protein had decreased stability. Each unaffected parent was heterozygous for the mutation, which was not found in 100 control chromosomes. Bessa et al. (2008) concluded that the mutant protein retained enzyme activity, which was consistent with the milder phenotype.
In affected members of a Dutch family with autosomal recessive spinocerebellar ataxia-7 (SCAR7; 609270), originally reported by Breedveld et al. (2004), Sun et al. (2013) identified compound heterozygous mutations in the TPP1 gene: a c.1397T-G transversion, resulting in a val466-to-gly (V466G) substitution at a highly conserved residue, and splice site mutation (c.509-1G-C; 607998.0004), resulting in a frameshift and premature termination (Val170GlyfsTer29). The mutations were found by whole-exome sequencing, confirmed by Sanger sequencing, and segregated with the disorder in the family. An unrelated Dutch woman with the disorder was also found to be compound heterozygous for these 2 mutations, although a founder effect could not be confirmed. Residual TPP1 activity in patient lymphocytes was 10 to 15% that of controls, with 5% activity in patient fibroblasts. Electron microscopic analysis of 1 of the affected family member's skin fibroblasts showed some granular osmiophilic deposits (GROD) and fingerprint profiles, but no curvilinear profiles. Analysis of the unrelated Dutch woman's fibroblasts showed no abnormalities. Sun et al. (2013) suggested that V466G yields a hypomorphic allele with residual functional TPP1 activity, which likely resulted in a later age at onset and less severe phenotype in patients with SCAR7 compared to patients with neuronal ceroid lipofuscinosis-2 (CLN2; 204500).
In an 11-year-old girl with autosomal recessive spinocerebellar ataxia-7 (SCAR7; 609270), Dy et al. (2015) identified compound heterozygous mutations in the TPP1 gene: a c.1029G-C transversion resulting in a glu343-to-asp (E343D) substitution at a highly conserved residue, and the common splice site mutation (c.509-1G-C; 607998.0004). The mutations were found by whole-exome sequencing. TPP1 activity in patient cells was significantly decreased (3 to 15%) compared to controls.
In 2 sibs, born to consanguineous parents, with neuronal ceroid lipofuscinosis-2 (CLN2; 204500), Steigerwald et al. (2023) identified a homozygous splice site mutation (c.1146-199G-A, NM_000391.3) in intron 9 of the TPP1 gene, resulting in abnormal splicing. The mutation, which was identified by long-read sequencing of the TPP1 gene, was present in heterozygous state in the unaffected parents. TPP1 enzyme activity was absent in leukocytes from one of the sibs and in a CVS sample and blood spot from the other sib. RNA sequencing in blood from one of the sibs demonstrated that the mutation resulted in retention of 84 basepairs from intron 9.
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