CTSF

protein-coding

cathepsin F, the group of Cathepsins

Gene summary

Cathepsins are papain family cysteine proteinases that represent a major component of the lysosomal proteolytic system. Cathepsins generally contain a signal sequence, followed by a propeptide and then a catalytically active mature region. The very long (251 amino acid residues) proregion of the cathepsin F precursor contains a C-terminal domain similar to the pro-segment of cathepsin L-like enzymes, a 50-residue flexible linker peptide, and an N-terminal domain predicted to adopt a cystatin-like fold. The cathepsin F proregion is unique within the papain family cysteine proteases in that it contains this additional N-terminal segment predicted to share structural similarities with cysteine protease inhibitors of the cystatin superfamily. This cystatin-like domain contains some of the elements known to be important for inhibitory activity. CTSF encodes a predicted protein of 484 amino acids which contains a 19 residue signal peptide. Cathepsin F contains five potential N-glycosylation sites, and it may be targeted to the endosomal/lysosomal compartment via the mannose 6-phosphate receptor pathway. The cathepsin F gene is ubiquitously expressed, and it maps to chromosome 11q13, close to the gene encoding cathepsin W. [provided by RefSeq, Jul 2008]

MANE transcript

NM_003793.4

Inheritance

ClinVar variants

P:45U:135B:67

Top phenotype

Neuronal ceroid lipofuscinosis 13

gnomAD constraint

pLI —, LoF o/e 0.84

Max pathogenic AF

—

Genomic locus

chr11:66,563,464-66,568,879

External References & Databases

Ensembl (ENSG00000174080)

Transcript & Mutation Effects

hg38 • Region Span ~5.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neuronal ceroid lipofuscinosis 13STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014147

Submitter: Labcorp Genetics (formerly Invitae)

neuronal ceroid lipofuscinosis 13STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014147

Submitter: Genomics England PanelApp

neuronal ceroid lipofuscinosis 13LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0014147

Submitter: Labcorp Genetics (formerly Invitae)

neuronal ceroid lipofuscinosis 13SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014147

Submitter: Orphanet

adult neuronal ceroid lipofuscinosisDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019260

Submitter: ClinGen

The neuronal ceroid lipofuscinoses (NCL) are a heterogeneous group of progressive neurodegenerative disorders characterized by the intracellular accumulation of autofluorescent storage material. Biallelic pathogenic variants in *CTSF* cause neuronal ceroid lipofuscinosis, type 13 (NCL13) or Kufs disease type B, an adult-onset form of NCL without reported retinal disease. Kufs disease type B is characterized by progressive cognitive decline, tremor, ataxia, myoclonus, rigidity, perioral dyskinesias, dysarthria, seizures, hyperreflexia, and behavior changes. Affected individuals may be diagnosed with frontotemporal dementia. Onset of symptoms in reported individuals ranges from the third to sixth decade and affected individuals demonstrate cerebral and cerebellar atrophy on MRI and the characteristic autofluorescent storage bodies in a variety of cell types. *CTSF* encodes for cathepsin F, a lysosomal cysteine protease, and the disease mechanism is loss of function. Fifteen different disease-causing variants have been reported in families in the literature, in the homozygous or compound heterozygous state. The pathogenic variant spectrum includes nonsense, frameshift, canonical splice site, missense variants, and a multi-exonic deletion (Smith et al, PMID 23297359; Di Fabio et al, PMID 25274848; Bras et al, PMID 27524508; van der Zee et al, PMID 27668283; Blauwendraat et al, PMID 28749476; Wang et al, PMID 29120254; Kulkarni et al, PMID 33578366; Wagner et al, PMID 34561610; Gultekin et al, PMID 35139754). A number of the reported families demonstrate complete co-segregation of the *CTSF* variants with disease, and one family from a small isolated Italian community demonstrates pseudo-dominant inheritance (Smith et al, PMID 23297359; van der Zee et al, PMID 27668283; Di Fabio et al, PMID 25274848). Supporting experimental evidence includes a non-human model organism; a Ctsf deficient mouse model that developed neurological disease comparable to the human phenotype and an accumulation of autofluorescent granules in brain tissue (Tang et al, 16508006; Smith et al, PMID 23297359). Case level genetic evidence provides a score of 12 points and experimental evidence provides a score of 2 points, resulting in a total score of 14 points. Evidence supporting an association between *CTSF* and NCL has been replicated over time; therefore, the gene-disease validity has been classified as DEFINITIVE. This classification was approved by the ClinGen Epilepsy GCEP on March 1, 2022 (SOP Version 8).

neuronal ceroid lipofuscinosis 13DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014147

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Neuronal ceroid lipofuscinosis 13AR

Manifestation: Biochemical; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 20301601; 23297359

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CTSF variants in ClinVar

9 Conditions Cataloged

Neuronal ceroid lipofuscinosis 13Total: 155

Inborn genetic diseasesTotal: 120

not providedTotal: 115

not specifiedTotal: 33

CTSF-related disorderTotal: 20

Neuronal ceroid lipofuscinosisTotal: 9

Neurodevelopmental disorderTotal: 2

Developmental disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003793.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				50 clinvar	1 clinvar	51
missense	3 clinvar	4 clinvar	129 clinvar	14 clinvar	2 clinvar	152
nonsense	4 clinvar	5 clinvar	2 clinvar			11
start loss						0
frameshift	7 clinvar	13 clinvar	2 clinvar			22
splice donor/acceptor (+/-2bp)	1 clinvar	8 clinvar	2 clinvar			11
Total	15	30	135	64	3	247

Highest pathogenic variant AF is 0.00004379474

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 59 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003793.4	RefSeq	NP_003784.2	13	MANE Select
ENST00000310325.10	Ensembl	ENSP00000310832.5	13	MANE Select
ENST00000524994.6	Ensembl	ENSP00000433082.2	13	Standard
ENST00000524994.7	Ensembl	ENSP00000433082.2	13	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Lysosome - Homo sapiens (human)
Apoptosis - Homo sapiens (human)
MHC class II antigen presentation
Immune System
Adaptive Immune System

Biological Process

proteolysis
antigen processing and presentation of exogenous peptide antigen via MHC class II
proteolysis involved in cellular protein catabolic process

Molecular Function

cysteine-type endopeptidase activity

Cellular Component

extracellular space
lysosome
lysosomal lumen
extracellular exosome
extracellular vesicle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000310325
Coding exons: 13
Length: 5379
Individuals with no LoFs: 125693
Homozygous LoFs: 0
Heterozygous LoFs: 55
Defined: 125748
p: 0.000219

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.744	217	250	0.868	0.0000145	3086
Missense (PolyPhen)		88	113.43	0.7758		1329
Synonymous	-0.246	105	102	1.03	0.00000625	959
Loss of Function	0.753	22	26.2	0.841	0.00000121	304

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00043	0.00043	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00088	0.00087	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00013	0.00013	rare
South Asian	0.00039	0.00039	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Thiol protease which is believed to participate in intracellular degradation and turnover of proteins. Has also been implicated in tumor invasion and metastasis.;

Recessive Scores

pRec: 0.152

Intolerance Scores

LoFtool: 0.466
RVIS EVS: 0.49
RVIS percentile EVS: 79.46

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.199

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium