CTSK

protein-coding

cathepsin K, the group of Cathepsins

Gene summary

The protein encoded by this gene is a lysosomal cysteine proteinase involved in bone remodeling and resorption. This protein, which is a member of the peptidase C1 protein family, is predominantly expressed in osteoclasts. However, the encoded protein is also expressed in a significant fraction of human breast cancers, where it could contribute to tumor invasiveness. Mutations in this gene are the cause of pycnodysostosis, an autosomal recessive disease characterized by osteosclerosis and short stature. [provided by RefSeq, Apr 2013]

Previous symbols:

CTSO2
CTSO
PYCD

MANE transcript

NM_000396.4

Inheritance

ClinVar variants

P:151U:98B:112

Top phenotype

Pycnodysostosis

gnomAD constraint

pLI —, LoF o/e 0.55

Max pathogenic AF

—

Genomic locus

chr1:150,794,880-150,809,577

External References & Databases

Ensembl (ENSG00000143387)

Transcript & Mutation Effects

hg38 • Region Span ~14.7 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

pycnodysostosisDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009940

Submitter: ClinGen

CTSK was first reported in relation to pycnodysostosis, an autosomal recessive lysosomal storage disorder, in 1996 (Gelb BD, et al., 1996, PMID: 8703060). CTSK encodes cathepsin K, a member of the papain family of cysteine proteinases, which plays an important role in osteoclast function. A deficiency of cathepsin K results in an increase of demineralized bone surrounding individual osteoclasts as they do not adequately degrade the organic matrix. Accumulation of bone matrix around the osteoclasts causes various symptoms including short stature, characteristic facial appearance (convex nasal ridge and small jaw with obtuse mandibular angle), osteosclerosis with increased bone fragility, acro-osteolysis of the distal phalanges, delayed closure of the cranial sutures, and dysplasia of the clavicle. The diagnosis of pycnodysostosis is established by characteristic clinical and radiographic features and/or biallelic pathogenic variants in CTSK identified by molecular genetic testing (Leblanc S, et al., 2020, PMID: 33151655). Ten variants (5 missense, 1 splice site, 4 nonsense) that have been reported in nine probands in six publications (Gelb BD, et al., 1996, PMID: 8703060; Hou WS, et al., 1999, PMID: 10074491; Haagerup A, et al., 2000, PMID: 10878663; Markova TV, et al., 2022, PMID: 35315254; Arman A, et al., 2014, PMID: 24767306; Johnson MR, et al., 1996, PMID: 8938428), as well as one family with segregation information (Johnson MR, et al., 1996, PMID: 8938428), are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is loss of function. This gene-disease relationship is also supported by experimental evidence including biochemical function of cathepsin K, animal models systems, and expression data. Individuals with pycnodysostosis show decreased degradation of the bone matrix proteins, leading to increased bone density due to the absence of cathepsin K (Bossard MJ, et al., 1996, PMID: 8647860). Knockout mouse models recapitulate most of the ultrastructural, histological, and radiological abnormalities observed in humans with pycnodystosis including osteopetrosis, enhanced bone fragility, predisposition to bone fractures, reduced size of long bones (leading to short stature), bone marrow hypoplasia, splenomegaly (although rare in humans), and craniofacial anomalies (Saftig P, et al., 1998, PMID: 9811821; Gowen M, et al., 1999, PMID: 10491212). The cathepsin K mRNA and protein appeared to be compartmentalized toward the membrane as visualized by the localization of the in-situ hybridization signal and immunoreactivity in osteoclastic cells (Littlewood-Evans A, et al., 1997, PMID: 9028530). In summary, CTSK is definitively associated with pycnodysostosis. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

pycnodysostosisDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009940

Submitter: Natera

pycnodysostosisSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009940

Submitter: Genomics England PanelApp

pycnodysostosisSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009940

Submitter: Orphanet

pycnodysostosisDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009940

Submitter: Myriad Women's Health

pycnodysostosisDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009940

Submitter: G2P

pycnodysostosisSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009940

Submitter: Labcorp Genetics (formerly Invitae)

pycnodysostosisDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009940

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

PycnodysostosisAR

Manifestation: Biochemical; Craniofacial; Musculoskeletal

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: 14041831; 14470123; 1611757; 8703060; 9529353; 10074491; 15070910; 17397052; 19674475; 20305575; 21099701

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CTSK variants in ClinVar

25 Conditions Cataloged

not providedTotal: 302

PyknodysostosisTotal: 189

Inborn genetic diseasesTotal: 33

not specifiedTotal: 19

CTSK-related disorderTotal: 9

Obtuse angle of mandibleTotal: 1

Abnormal skull morphologyTotal: 1

ScoliosisTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000396.4. 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			7 clinvar	107 clinvar		114
missense	4 clinvar	25 clinvar	90 clinvar	5 clinvar		124
nonsense	6 clinvar	22 clinvar				28
start loss	1 clinvar	2 clinvar				3
frameshift	33 clinvar	36 clinvar				69
splice donor/acceptor (+/-2bp)	5 clinvar	17 clinvar	1 clinvar			23
Total	49	102	98	112	0	361

Highest pathogenic variant AF is 0.00017409277

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 33 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000396.4	RefSeq	NP_000387.1	7	MANE Select
ENST00000271651.8	Ensembl	ENSP00000271651.3	7	MANE Select
ENST00000443913.2	Ensembl	ENSP00000405083.2	8	Standard
ENST00000443913.3	Ensembl	ENSP00000405083.2	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Lysosome - Homo sapiens (human)
Toll-like receptor signaling pathway - Homo sapiens (human)
Rheumatoid arthritis - Homo sapiens (human)
Osteoclast differentiation - Homo sapiens (human)
Apoptosis - Homo sapiens (human)

Biological Process

autophagy of mitochondrion
intramembranous ossification
proteolysis
extracellular matrix disassembly
collagen catabolic process

Molecular Function

fibronectin binding
cysteine-type endopeptidase activity
serine-type endopeptidase activity
protein binding
collagen binding

Cellular Component

extracellular region
extracellular space
nucleoplasm
lysosome
endolysosome lumen

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000271651
Coding exons: 7
Length: 12116
Individuals with no LoFs: 125696
Homozygous LoFs: 0
Heterozygous LoFs: 52
Defined: 125748
p: 0.000207

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.998	134	171	0.785	0.00000888	2168
Missense (PolyPhen)		58	78.319	0.74056		934
Synonymous	0.663	57	63.7	0.894	0.00000321	614
Loss of Function	1.75	10	18.0	0.554	0.00000102	211

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.00043	0.00043	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00025	0.00025	rare
South Asian	0.000098	0.000098	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Closely involved in osteoclastic bone resorption and may participate partially in the disorder of bone remodeling. Displays potent endoprotease activity against fibrinogen at acid pH. May play an important role in extracellular matrix degradation.;

Recessive Scores

pRec: 0.0995

Intolerance Scores

LoFtool: 0.302
RVIS EVS: -0.34
RVIS percentile EVS: 30.07

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.222

Gene Damage Prediction

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