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. 2019 Nov;40(11):1924-1938.
doi: 10.1002/humu.23860. Epub 2019 Jul 26.

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

Emily Gardner  1 , Mitch Bailey  2 , Angela Schulz  3 , Mikel Aristorena  1 , Nicole Miller  2 , Sara E Mole  1
Affiliations

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

Emily Gardner et al. Hum Mutat. 2019 Nov.

Abstract

Neuronal ceroid lipofuscinosis type 2 (CLN2 disease) is an autosomal recessive condition caused by variants in the TPP1 gene, leading to deficient activity of the lysosomal enzyme tripeptidyl peptidase I (TPP1). We update on the spectrum of TPP1 variants associated with CLN2 disease, comprising 131 unique variants from 389 individuals (717 alleles) collected from the literature review, public databases, and laboratory communications. Previously unrecorded individuals were added to the UCL TPP1-specific database. Two known pathogenic variants, c.509-1 G>C and c.622 C>T (p.(Arg208*)), collectively occur in 60% of affected individuals in the sample, and account for 50% of disease-associated alleles. At least 86 variants (66%) are private to single families. Homozygosity occurs in 45% of individuals where both alleles are known (87% of reported individuals). Atypical CLN2 disease, TPP1 enzyme deficiency with disease onset and/or progression distinct from classic late-infantile CLN2, represents 13% of individuals recorded with associated phenotype. NCBI ClinVar currently holds records for 37% of variants collected here. Effective CLN2 disease management requires early diagnosis; however, irreversible neurodegeneration occurs before a diagnosis is typically reached at age 5. Timely classification and public reporting of TPP1 variants is essential as molecular testing increases in use as a first-line diagnostic test for pediatric-onset neurological disease.

Keywords: genotype-phenotype correlation; late-infantile neuronal ceroid lipofuscinosis; lysosomal storage disorders; neurodegeneration; tripeptidyl peptidase I.

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Conflict of interest statement

A. Schulz has received personal fees from BioMarin Pharmaceutical Inc., outside of the submitted work. M. Aristorena has no conflicts of interest to declare. M. Bailey was an employee of BioMarin Pharmaceutical Inc. at the time of the study. N. Miller was an employee of BioMarin Pharmaceutical Inc. at the time of the study. Professor S. E. Mole receives financial support from BioMarin Pharmaceutical Inc. to maintain the NCL Mutation Database and acts as an advisor to BioMarin Pharmaceutical Inc. on mutations in TPP1.

Figures

Figure 1
Figure 1
Spectrum of TPP1 variants described
Figure 2
Figure 2
TPP1 gene structure and variants reported>two times. Domain information from InterPro accession O14773. Numbers within the arrows are the frequency with which variants were reported in the registry
Figure 3
Figure 3
Most common alleles listed in the TPP1 locus‐specific database by region of origin. The number of times an allele was encountered is shown in parentheses. North America includes Newfoundland. Note: The emphasis now is on collecting new variants; frequency of the most common variants is, therefore, underrepresented here as new reports for these are no longer included in the UCL TPP1 locus‐specific database.
Figure 4
Figure 4
TPP1 proenzyme structure and missense variants reported ≥ three times. Three‐dimensional structure of TPP1 dimers (Pal et al., 2009). Active site (catalytic triad, Ser475‐Glu272‐Asp360) pocket residues are shown as red space‐filling models, calcium binding sites (Asp517‐Val518‐Gly539‐Asp543) in blue.
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