CTSD

protein-coding

cathepsin D, the group of Cathepsins|Peptidase family A1

Gene summary

This gene encodes a member of the A1 family of peptidases. The encoded preproprotein is proteolytically processed to generate multiple protein products. These products include the cathepsin D light and heavy chains, which heterodimerize to form the mature enzyme. This enzyme exhibits pepsin-like activity and plays a role in protein turnover and in the proteolytic activation of hormones and growth factors. Mutations in this gene play a causal role in neuronal ceroid lipofuscinosis-10 and may be involved in the pathogenesis of several other diseases, including breast cancer and possibly Alzheimer's disease. [provided by RefSeq, Nov 2015]

Previous symbols:

CPSD

MANE transcript

NM_001909.5

Inheritance

ClinVar variants

P:56U:234B:255

Top phenotype

Ceroid lipofuscinosis, neuronal, 10

gnomAD constraint

pLI —, LoF o/e 0.44

Max pathogenic AF

—

Genomic locus

chr11:1,752,752-1,764,573

External References & Databases

Ensembl (ENSG00000117984)

Transcript & Mutation Effects

hg38 • Region Span ~11.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neuronal ceroid lipofuscinosis 10STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012414

Submitter: Genomics England PanelApp

neuronal ceroid lipofuscinosis 10STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012414

Submitter: Labcorp Genetics (formerly Invitae)

neuronal ceroid lipofuscinosisDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016295

Submitter: ClinGen

The neuronal ceroid lipofuscinoses (NCL) are a heterogeneous group of progressive neurodegenerative disorders characterized by the intracellular accumulation of auto-fluorescent storage material. Biallelic pathogenic variants in CTSD are causative of neuronal ceroid lipofuscinosis, type 10 (NCL10). NCL10 is characterized by acquired microcephaly, developmental regression, seizures, ataxia, cardiomyopathy and retinitis pigmentosa. Onset of symptoms can range from the prenatal period to the second decade and affected individuals demonstrate cerebral and cerebellar atrophy on MRI, significantly reduced cathepsin D enzyme activity in leukocytes or fibroblasts and the characteristic autofluorescent storage bodies in a variety of cell types. The disease mechanism is loss of function and CTSD mutations result in a significantly reduced cathepsin D, a lysosomal aspartyl proteinase essential to neuronal cell homeostasis. Over 10 different disease-causing mutations reported in families in the literature, the majority of which are homozygous variants identified in consanguineous families. The mutation spectrum includes nonsense, frameshift, and missense variants (Doccini et al, PMID 27072142; Steinfeld et al, PMID 16685649; Thottath et al, PMID 31086824; Hersheson et al, PMID 25298308; Fokstuen et al, PMID 27353043; Varvagiannis et al, PMID 29284168; Meyer et al, PMID 26059544; Komlosi et al, PMID 29373990; Sintola et al, PMID 16670177; Seidahmed et al, PMID 23101555; Alazami et al, PMID 25558065; Shaheen et al, PMID 30214071; Fritchie et al, PMID 18762956; Santorelli et al, PMID 23374165). Missense variant point assignment was upgraded due to functional data and/or the presence of the variant in individuals with proven reduced cathepsin D enzyme activity. Additionally, a number of reported families demonstrate complete co-segregation in affected and unaffected individuals. Supporting experimental evidence includes functional alteration in non-patient cells (Paranen et al, PMID 12350228), expression (Reid et al, 3543065), non-human model organism (Tyynela et al, 10856224 ; Koike et al, 10995834 ; Awano et al, 16386934), and rescue in non-human model organism (Marques et al, 31282275). A genetic evidence score of 12 and experimental evidence score of 5 results in a total score of 17. Evidence supporting an association between CTSD and NCL has been replicated over time; therefore, the gene-disease validity has been classified as DEFINITIVE.

neuronal ceroid lipofuscinosis 10DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012414

Submitter: G2P

Clinical Genomic Database (CGD)

Ceroid lipofuscinosis, neuronal, 10AR

Manifestation: Biochemical; Neurologic; Ophthalmologic

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: 16670177; 16685649; 25298308

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CTSD variants in ClinVar

10 Conditions Cataloged

Neuronal ceroid lipofuscinosisTotal: 666

not providedTotal: 135

not specifiedTotal: 123

Inborn genetic diseasesTotal: 107

Neuronal ceroid lipofuscinosis 10Total: 61

CTSD-related disorderTotal: 28

Severe microlissencephalyTotal: 1

Retinal disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001909.5. 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			4 clinvar	237 clinvar	4 clinvar	245
missense	2 clinvar	3 clinvar	224 clinvar	14 clinvar		243
nonsense	8 clinvar	3 clinvar				11
start loss			1 clinvar			1
frameshift	21 clinvar	5 clinvar	4 clinvar			30
splice donor/acceptor (+/-2bp)		14 clinvar	1 clinvar			15
Total	31	25	234	251	4	545

Highest pathogenic variant AF is 0.000016734182

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 46 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001909.5	RefSeq	NP_001900.1	9	MANE Select
ENST00000236671.7	Ensembl	ENSP00000236671.2	9	MANE Select
ENST00000367196.4	Ensembl	ENSP00000356164.4	8	Standard
ENST00000367196.5	Ensembl	ENSP00000356164.4	8	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
ctsd	Danio rerio	Structure: muscle Quality: decreased thickness abnormal

Gene / Model

Organism

Observed Phenotype

ctsd

Danio rerio

Structure: muscle

Quality: decreased thickness

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Autophagy - animal - Homo sapiens (human)
Lysosome - Homo sapiens (human)
Estrogen signaling pathway - Homo sapiens (human)
Tuberculosis - Homo sapiens (human)
Sphingolipid signaling pathway - Homo sapiens (human)

Biological Process

proteolysis
antigen processing and presentation of exogenous peptide antigen via MHC class II
protein catabolic process
collagen catabolic process
neutrophil degranulation

Molecular Function

aspartic-type endopeptidase activity
cysteine-type endopeptidase activity
serine-type endopeptidase activity
protein binding

Cellular Component

extracellular region
extracellular space
lysosome
specific granule lumen
melanosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000236671
Coding exons: 9
Length: 11241
Individuals with no LoFs: 125700
Homozygous LoFs: 0
Heterozygous LoFs: 16
Defined: 125716
p: 0.0000636

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.38	190	252	0.755	0.0000168	2648
Missense (PolyPhen)		72	110.36	0.65239		1123
Synonymous	-0.909	134	121	1.10	0.00000958	865
Loss of Function	2.21	8	18.2	0.441	8.85e-7	210

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.000090	0.000088	rare
South Asian	0.000066	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Acid protease active in intracellular protein breakdown. Plays a role in APP processing following cleavage and activation by ADAM30 which leads to APP degradation (PubMed:27333034). Involved in the pathogenesis of several diseases such as breast cancer and possibly Alzheimer disease. {ECO:0000269|PubMed:27333034}.;
Disease: DISEASE: Ceroid lipofuscinosis, neuronal, 10 (CLN10) [MIM:610127]: A form of neuronal ceroid lipofuscinosis with onset at birth or early childhood. Neuronal ceroid lipofuscinoses are progressive neurodegenerative, lysosomal storage diseases characterized by intracellular accumulation of autofluorescent liposomal material, and clinically by seizures, dementia, visual loss, and/or cerebral atrophy. {ECO:0000269|PubMed:16670177, ECO:0000269|PubMed:16685649, ECO:0000269|PubMed:21990111}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.909

Intolerance Scores

LoFtool: 0.533
RVIS EVS: -0.58
RVIS percentile EVS: 18.72

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.970

Gene Damage Prediction

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